Resolvin D1 attenuates imiquimod-induced mice psoriasiform dermatitis through MAPKs and NF-κB pathways.
Xu Juntao,Duan Xiaoru,Hu Feng,Poorun Devesh,Liu Xinxin,Wang Xin,Zhang Song,Gan Lu,He Mengwen,Zhu Ke,Ming Zhangyin,Chen Hongxiang
Journal of dermatological science
BACKGROUND:Resolvin D1 (RvD1), a pro-resolution lipid mediator derived from docosahexaenoic acid (DHA), has been described to promote several kinds of inflammatory resolution. However, the effects and anti-inflammatory mechanisms of RvD1 on psoriasis have not been previously reported. OBJECTIVE:The present study aimed to determine the protective effects and the underlying mechanisms of RvD1 on imiquimod (IMQ)-induced psoriasiform dermatitis. METHODS:Mice were topically treated with IMQ to develop psoriasiform dermatitis on their shaved back, pretreated intraperitoneally (i.p.) with or without RvD1 or tert-butoxycarbonyl Met-Leu-Phe peptide (Boc), a lipoxin A4 (ALX) receptor antagonist. The severity was monitored and graded using a modified human scoring system, the Psoriasis Area and Severity Index (PASI), histopathology, and the signature cytokines of psoriasis (IL-23, IL-17, IL-22 and TNF-α). The mRNA and protein levels of inflammatory cytokines were quantified by quantitative real-time PCR (QRT-PCR) and ELISA. The expressions of signaling proteins MAPKs and NF-κB p65 were analyzed using western blotting. Electrophoretic mobility shift assay (EMSA) was used to check NF-κB p65 DNA binding activity. RESULTS:Our study showed that RvD1 alleviated IMQ-induced psoriasiform dermatitis and improved skin pathological changes. RvD1 markedly inhibited IMQ-induced activation of ERK1/2, p38, JNK (c-Jun N-terminal protein kinase, a subfamily of MAPKs), and NF-κB. Furthermore, pretreatment with Boc, would not exacerbate skin inflammation of IMQ-induced mice, but significantly reversed the beneficial effects of RvD1 on IMQ-induced psoriasiform inflammation. CONCLUSION:RvD1 can obviously improve skin inflammation in IMQ-induced mice psoriasiform dermatitis. The protective mechanisms might be related to its selective reaction with lipoxin A4 receptor/Formyl-peptide receptor 2 (ALX/FPR2), by downregulating relevant cytokines of the IL-23/IL-17 axis expression, the inhibition of MAPKs and NF-κB signaling transduction pathways. Thus, these results show that RvD1 could be a possible candidate for psoriasis therapy.
Expression of NLPR3 in Psoriasis Is Associated with Enhancement of Interleukin-1β and Caspase-1.
Su Fei,Xia Yun,Huang Meng,Zhang Liang,Chen Liuqing
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND NLPR3 is an important gene that belongs to the family of NOD-like receptors and is thought to play an important role in psoriasis. The aim of the present study was to investigate the expression of NLRP3 in psoriasis biopsy samples and to assess the possible correlation of its expression with that of interleukin IL-1β and Caspase-1. MATERIAL AND METHODS The mRNA expression was checked by qRT-PCR. The expression of the proteins was checked by Western blotting. The distribution of the proteins was determined by immunohistochemistry. RESULTS The results of our study indicate that the expression of NLRP3 was significantly upregulated in all the psoriatic biopsy samples as indicated by qRT-PCR and Western blotting. The expression of NLRP3 in psoriatic samples was 3.5 to 4.3 times higher than the expression of NLRP3 in normal skin biopsy samples. Moreover, our results indicated that the expression levels of IL-1β were higher as compared to the normal skin biopsy samples. Relative to the expression of IL-1β in normal skin biopsy samples, the expression of IL-1b was about 2.7-4.6 times higher. Additionally, the expression of caspase-1 was considerably upregulated in the psoriatic samples. Caspase-1 gene expression was 2.2-3.4 times higher than in normal skin biopsy samples. CONCLUSIONS NLPR3 may prove to be an important therapeutic target for psoriasis.
TRB3 is elevated in psoriasis vulgaris lesions and mediates HaCaT cells proliferation in vitro.
Yu Xiao-Jing,Song Tie-Jun,Zhang Lu-Wei,Su Ying,Wang Ke-Yu,Sun Qing
Journal of investigative medicine : the official publication of the American Federation for Clinical Research
Psoriasis is a chronic skin disease characterized by abnormal keratinocyte proliferation and differentiation, inflammation, and angiogenesis. Overexpression of tribbles homolog3 (TRB3), which belongs to the tribbles family of pseudokinases, has been found in several human tumors and metabolic diseases, but its role in psoriasis has not been fully clarified. The aim of this study is to investigate the expression of TRB3 in psoriasis and explore its roles in the proliferation of keratinocytes. Twenty-four patients with psoriasis vulgaris were recruited for the study. Diagnosis of psoriasis was based on clinical and histologic examinations. Immunohistochemistry and real-time reverse transcription PCR (RT-PCR) were performed to determine protein and messenger RNA (mRNA) expression of TRB3 in psoriasis lesions. 5-Bromo-2-deoxyUridine (BrdU) incorporation assay were performed for cell proliferation. Cell cycle distribution was assessed by flow cytometry analysis. The levels of TRB3 is elevated in psoriatic lesions compared with psoriatic non-lesions. The HaCat cells expressed the TRB3 gene. We found TRB3 silencing to significantly inhibit HaCat cell proliferation. Furthermore, the specific knockdown of TRB3 slowed down the cell cycle at the gap 0/first gap phase. In conclusion, our data suggest that TRB3 is overexpressed in lesions of patients with psoriasis and may be involved in the abnormal proliferation of keratinocytes. Therefore, TRB3 may be a potential therapeutic target for psoriasis.
Proanthocyanidins: novel treatment for psoriasis that reduces oxidative stress and modulates Th17 and Treg cells.
Lai Rui,Xian Dehai,Xiong Xia,Yang Lingyu,Song Jing,Zhong Jianqiao
Redox report : communications in free radical research
Psoriasis is a common, chronic, inflammatory skin disease that affects 2%-4% of the global population. Recent studies have shown that increased oxidative stress (OS) and T-cell abnormalities are central to the pathogenesis of this disease. The resulting reactive oxygen species (ROS) induces proliferation and differentiation of Th17/Th1/Th22 cells and inhibits the anti-inflammatory activities of regulatory T lymphocytes (Treg). Subsequent secretions of inflammatory cytokines, such as interleukin (IL)-17, IL-22, tumor necrosis factor alpha (TNF-α), and interferon-gamma (IFN-γ), and vascular endothelial growth factor (VEGF), stimulate keratinocyte proliferation and angiogenesis. Proanthocyanidins are a class of flavonoids from plants and fruits, and have various antioxidant, anti-inflammatory, and anti-angiogenic properties. Numerous reports have demonstrated therapeutic effects of proanthocyanidins for various diseases. Among clinical activities, proanthocyanidins suppress cell proliferation, prevent OS, and regulate Th17/Treg cells. Because the pathogenesis of psoriasis involves OS and T cells dysregulation, we reviewed the effects of proanthocyanidins on OS, Th17 and Treg cell activities, and keratinocyte proliferation and angiogenesis. Data from multiple previous studies warrant consideration of proanthocyanidins as a promising strategy for the treatment of psoriasis.
Abnormal expression of SIRTs in psoriasis: Decreased expression of SIRT 1-5 and increased expression of SIRT 6 and 7.
Fan Xiaojing,Yan Kexiang,Meng Qinqin,Sun Rui,Yang Xinrong,Yuan Dingfen,Li Fulun,Deng Hui
International journal of molecular medicine
The prevalence of psoriasis is increasing, and poses a serious risk to human health and quality of life. Psoriasis, a chronic immune‑mediated skin disease with epidermal hyperkeratosis and parakeratosis, is associated with numerous complications, including metabolic syndromes that are regulated by sirtuins (SIRTs) via deacetylation. As they serve a necessary function in inflammation and metabolism, SIRTs are considered to link inflammation and metabolic syndrome. Previous studies have indicated that SIRTs serve a function in the pathophysiology of psoriasis, but to date no detailed research has been conducted investigating the expression levels and patterns of SIRTs in psoriasis. The present study investigated the abnormal expression of SIRTs in psoriasis and provided a theoretical foundation for the treatment and prognosis of psoriasis. Tumor necrosis factor (TNF)‑α‑stimulated HaCaT cells and an imiquimod‑induced psoriasis mouse model were used to produce in vitro and in vivo models, respectively. Psoriasis clinical specimens (psoriasis area and severity index >10; n=22) and normal group specimens (n=22) were obtained from human subjects. The mRNA and protein expression levels in human and mouse skin lesions and TNF‑α‑stimulated HaCaT cells were detected using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting, and compared with the control groups. The expression patterns of SIRT proteins were investigated using immunofluorescence (IF) staining. The expression levels of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 were downregulated while those of SIRT6 and SIRT7 were upregulated in skin lesions and TNF‑α‑stimulated HaCaT cells compared with the control group as determined by RT‑qPCR, western blotting and IF. Statistically significant differences were observed in vivo and in vitro. P‑values of SIRT1‑7 mRNA are less than 0.05 in RT‑qPCR, and the P‑values of SIRT1‑7 proteins are less than 0.05 except for SIRT4 in the western blot analysis. SIRTs serve notable functions in severe psoriasis dermatitis, with the overexpression of SIRT6 and SIRT7 potentially induced by the adaptive immune response, and the downregulation of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 may be a result of an internal environment imbalance in vivo. Psoriasis is an inflammation and metabolism‑associated disease mediated by the SIRT family. The present results provide a novel potential mechanism and strategy for the treatment of psoriasis by modulating the function and expression of SIRTs.
GDF11 Antagonizes Psoriasis-like Skin Inflammation via Suppression of NF-κB Signaling Pathway.
Wang Wenhan,Qu Ruize,Wang Xi,Zhang Mengchen,Zhang Yayun,Chen Changjun,Chen Xiaomin,Qiu Cheng,Li Jiayi,Pan Xin,Li Weiwei,Zhao Yunpeng
Growth differentiation factor-11 (GDF11) is a key member of the transforming growth factor β (TGF-β) superfamily, which plays a momentous role in both normal physiological processes and pathophysiology processes. Recently, it was reported that GDF11 was closely associated with several inflammatory conditions and protected against development of inflammation. Psoriasis-like skin inflammation is a common skin inflammatory disease, yet much is unknown about the underlying mechanisms. In this study, we investigated the expression pattern of GDF11 in two psoriasis-like skin inflammation mice models and tumor necrosis factor-α (TNF-α)-induced RAW264.7 macrophages. Furthermore, RAW264.7 cell was cultured, and GDF11 antagonized the inflammatory function of TNF-α in vitro. Moreover, imiquimod-induced mice model and IL-23-induced mice model were established to investigate the anti-inflammatory role of GDF11 in vivo. As a result, the administration of GDF11 remarkably attenuated the severity of skin inflammation in both two mice models. Additionally, the activation of nuclear NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling pathway was repressed by GDF11 treatment. Collectively, GDF11 may represent a promising molecular target for the prevention and treatment of psoriasis-like skin inflammation.
Paeonol ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice by inhibiting the maturation and activation of dendritic cells.
Meng Yujiao,Wang Mingxing,Xie Xiangjiang,Di Tingting,Zhao Jingxia,Lin Yan,Xu Xiaolong,Li Ningfei,Zhai Yating,Wang Yan,Li Ping
International journal of molecular medicine
Paeonol, an active component derived from the traditional Chinese medicine Cortex Moutan, possesses anti-inflammatory, analgesic, antioxidant and anti-allergic properties. Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of Toll‑like receptors (TLRs) in dendritic cells (DCs), which are primarily responsible for initiating an immune response. We investigated the effect of paeonol on inflammation in an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by R848. Mice were intragastrically administered 100 mg/kg (high), 50 mg/kg (medium) and 25 mg/kg (low) paeonol, respectively. We evaluated inflammation of psori-asis‑like lesions based on histological changes, protein levels of myeloid differentiation factor 88 (MyD88) and TLR8 in skin lesions by western blotting, and levels of CD11c+ DCs in skin by immunoassay and in spleens by flow cytometry. Inflammatory cytokines [interleukin (IL)-23, IL-12 and IL-1β] in skin lesions and BMDCs were also assessed by RT-PCR and ELISA. Application of paeonol decreased IMQ-induced keratinocyte proliferation, and infiltration of CD3+ cells, while the treatment ameliorated CD11c+ cells in the spleen and skin, and reduced MyD88 and TLR8 proteins in skin lesions. Paeonol inhibited IMQ-induced mRNA expression of IL-23, but not IL-12 and IL-1β in BMDCs, along with significantly lower levels of DCs expressing MHCⅡ, CD80 and CD86 in vitro. These results indicate that paeonol suppresses the maturation and activation of DCs by decreasing MyD88 and TLR8 proteins in the TLR7/8 signaling pathway which finally alleviates psoriasis‑like skin lesions. The TLR7/8 signaling pathway in DCs provides an important insight into the mechanism of psoriasis, and paeonol may be a potent therapeutic drug for psoriasis.
microRNA-130a Promotes Human Keratinocyte Viability and Migration and Inhibits Apoptosis Through Direct Regulation of STK40-Mediated NF-κB Pathway and Indirect Regulation of SOX9-Meditated JNK/MAPK Pathway: A Potential Role in Psoriasis.
Xiong Ying,Chen Hongxiao,Liu Liqian,Lu Leihong,Wang Zongshan,Tian Fujun,Zhao Yongliang
DNA and cell biology
Psoriasis is a chronic inflammatory skin disorder. The aim of this study was to determine a potential role of microRNA (miR)-130a in psoriasis, and underlying mechanism. Expression levels of miR-130a in psoriasis specimens and normal skin tissues were analyzed. MiR-130a mimic, inhibitor, miR-control, small interfering RNA (siRNA) specific serine/threonine kinase 40 (STK40), or sex-determining region Y chromosome-box 9 (SOX9) were transfected to human keratinocyte HaCaT cells, respectively. After transfection, the cell viability, apoptosis, and migration were determined. Luciferase reporter assay, quantitative reverse transcription-polymerase chain reaction, and western blot were performed to explore whether STK40 was a target of miR-130a. The effects of aberrant expressions of miR-130a, STK40, or SOX9 on key proteins of NF-κB and c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) pathway were assessed. The miR-130a levels were significantly higher in patients with psoriasis compared to the healthy controls (p < 0.01). Overexpressing miR-130a strikingly promoted HaCaT cell viability and migration and inhibited apoptosis (p < 0.01 or p < 0.05). We confirmed that STK40 was a direct target of miR-130a, and STK40 was involved in miR-130a-induced cell functions. Overexpressing miR-130a significantly upregulated NF-κB p65, SOX9, p-c-Jun, p-JNK, and p-p38MAPK proteins and silencing miR-130a downregulated them. In addition, silencing STK40 alleviated the effects of anti-miR-130a on SOX9 expression. Furthermore, silencing SOX9 also decreased levels of p-c-Jun, p-JNK, and p-p38MAPK proteins. MiR-130a regulates human keratinocyte HaCaT viability, migration and apoptosis might be by direct regulation of STK40-mediated NF-κB pathway and by indirect regulation of SOX9-mediated downstream JNK/MAPK signaling pathway.
Silencing of miR‑155 suppresses inflammatory responses in psoriasis through inflammasome NLRP3 regulation.
Luo Quan,Zeng Jingxin,Li Wei,Lin Ling,Zhou Xin,Tian Xin,Liu Weiyu,Zhang Lidan,Zhang Xibao
International journal of molecular medicine
Psoriasis is a dermatosis with the major clinical symptoms of scale, erythema and itching, and it has a long disease course. In addition, it is easily recurrent and refractory, greatly affecting the physical and mental health of patients. In the present study, it was hypothesized that the function of miR‑155 increases psoriasis‑induced inflammation and that its expression may be dependent on inflammasome activation. miR‑155 expression was examined by gene chip array and quantitative polymerase chain reaction analysis. miR‑155 expression levels were significantly increased in an in vivo model of psoriasis compared with normal tissues, as was the expression of NLR family pyrin domain containing 3 (NLRP3). In vitro, using keratinocyte‑induced HaCaT cells as a model for psoriasis, silencing of miR‑155 was confirmed to significantly decrease inflammation and NLRP3/caspase‑1 signaling. Activation of toll‑like receptor 4 (TLR4) enhanced the miR‑155‑induced inflammatory response in the in vitro keratinocyte model. Treatment with a TLR4 inhibitor or an NLRP3 inhibitor reversed the miR‑155‑mediated inflammation in the same cell system. The present study demonstrated that miR‑155 silencing suppressed psoriasis‑associated inflammatory responses through inflammasome NLRP3 regulation.
miR-320b Is Down-Regulated in Psoriasis and Modulates Keratinocyte Proliferation by Targeting AKT3.
Wang Yan,Yu Xiaojing,Wang Lihua,Ma Weiyuan,Sun Qing
We investigated the molecular mechanisms underlying the role of miRNAs in the pathogenesis of psoriasis to discover novel potential diagnostic markers and treatment targets. We screened Chinese Han individuals using gene chip technology to identify differentially expressed miRNAs in the epidermal tissue of lesions from patients with psoriasis versus that from healthy controls. We also used bioinformatics methods and molecular biology experiments to predict and verify target genes and signaling pathways that may have an underlying role in normal human epidermal keratinocyte (NHEK) proliferation. Differentially expressed miRNAs were found in the epidermal tissue of lesions from patients with psoriasis; 45 were upregulated, and 71 were downregulated. Among them, miR-320b was significantly downregulated. Low miR-320b expression levels in NHEKs promoted cell proliferation. The luciferase assay results showed that AKT3 is a target gene of miR-320b. The protein phosphorylation levels of STAT3 and SAPK/JNK in the intracellular signaling pathway were significantly upregulated by miR-320b downregulation. Our findings indicate that miR-320b negatively regulates NHEK proliferation by targeting AKT3 to regulate the STAT3 and SAPK/JNK signaling pathways and might participate in the pathogenesis of psoriasis in Chinese Han populations. miR-320b may also be a novel diagnostic marker or therapeutic target for this disease.
miR-4516, a microRNA downregulated in psoriasis inhibits keratinocyte motility by targeting fibronectin/integrin α9 signaling.
Chowdhari Shruti,Sardana Kabir,Saini Neeru
Biochimica et biophysica acta. Molecular basis of disease
Psoriasis is recognized as a T cell mediated inflammatory hyperproliferative skin disorder. Several microRNAs (miRNAs) have been implicated in the pathogenesis of psoriasis however, understanding of their mechanistic involvement remains unclear. Previously, we have shown that PUVA induced miR-4516 downregulates signal transducer and activator of transcription 3 (STAT3) by direct binding to its 3' untranslated region (3'UTR) and suppresses STAT3 downstream genes (Bcl xl, Cyclin D1). Here, we demonstrate for the first time that expression of miR-4516 is significantly downregulated in psoriatic skin. We additionally validated extracellular matrix protein fibronectin 1 (FN1) and integrin subunit α9 (ITGA9) as direct targets of miR-4516. Interestingly, ITGA9 expression was found to be increased in the suprabasal psoriatic epidermis. We further showed that ectopic expression of miR-4516 in human keratinocytes not only suppresses cell motility and proliferation via significant downregulation of genes orchestrating cytoskeletal reorganization (Rac1, RhoA, Cdc42), but also inhibits F-actin assembly and induces terminal differentiation. Collectively, our results provide evidence that loss of expression of miR-4516 in psoriatic skin might be contributing to accelerated migration, resistance to apoptosis and differentiation as seen in psoriasis lesional keratinocytes and also highlight its potential as a novel small molecule for therapeutic intervention in psoriasis.
Polycystin-1 downregulation induces ERK-dependent mTOR pathway activation in a cellular model of psoriasis.
Gargalionis Antonios N,Malakou Lina S,Adamopoulos Christos,Piperi Christina,Theohari Irene,Nokhbehsaim Marjan,Deschner James,Kokkalis Georgios,Korkolopoulou Penelope,Papadavid Evangelia,Papavassiliou Athanasios G,Basdra Efthimia K
Biochimica et biophysica acta. Molecular basis of disease
Psoriatic plaques tend to localize to the knees and elbows, areas that are particularly subject to mechanical stress resulting from bending and friction. Moreover, plaques often develop at sites of mechanical trauma or injury (Koebner phenomenon). Nevertheless, mechanotransduction has never been linked to psoriasis. Polycystins (polycystin-1, PC1; polycystin-2, PC2) are mechanosensitive molecules that function as key regulators of cellular mechanosensitivity and mechanotransduction. The aim of this in vitro study was to investigate the role of polycystins in the development of psoriasis. We showed that PC1 knockdown in HaCaT cells led to an elevated mRNA expression of psoriasis-related biomarkers Ki-67, IL-6, TNF-α, VEGF and Bcl-2, while PC1 functional inhibition was accompanied by increased cell proliferation and migration of HaCaT cells. In addition, PC1 knockdown via siRNA in HaCaT cells was followed by activation of critical molecules of the mTOR and MAPK pathways and this mTOR pathway activation was ERK-dependent. Furthermore, loss of PC1 protein expression and elevated levels of activated mTOR substrates were also observed in human samples of psoriatic plaques. Overall, our study suggests that the PC1/ERK/mTOR signaling axis represents a novel potential mechanism in psoriasis pathogenesis.
IL-35 Decelerates the Inflammatory Process by Regulating Inflammatory Cytokine Secretion and M1/M2 Macrophage Ratio in Psoriasis.
Zhang Junfeng,Lin Yi,Li Chunlei,Zhang Xiaomei,Cheng Lin,Dai Lei,Wang Youcui,Wang Fangfang,Shi Gang,Li Yiming,Yang Qianmei,Cui Xueliang,Liu Yi,Wang Huiling,Zhang Shuang,Yang Yang,Xiang Rong,Li Jiong,Yu Dechao,Wei Yuquan,Deng Hongxin
Journal of immunology (Baltimore, Md. : 1950)
IL-35 downregulates Th17 cell development and suppresses certain types of autoimmune inflammation such as collagen-induced arthritis and experimental autoimmune uveitis. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells. However, the role of IL-35 in psoriasis remains unclear. In this study, we assessed IL-35 in three well-known psoriasis models: a human keratinocyte cell line (HaCaT), a keratin 14 (K14)-vascular endothelial growth factor A (VEGF-A)-transgenic (Tg) mouse model, and an imiquimod-induced psoriasis mouse model. First, we found that IL-35 suppressed the expression of IL-6, CXCL8, and S100A7, which are highly upregulated by a mixture of five proinflammatory cytokines in HaCaT. Second, a plasmid coding for the human IL-35 sequence coated with cationic liposomes showed potent immunosuppressive effects on K14-VEGF-A-Tg and imiquimod-induced psoriasis mouse models. In the K14-VEGF-A-Tg model, our results showed that several types of proinflammatory cytokines were significantly reduced, whereas IL-10 was remarkably induced by IL-35. Compared with pcDNA3.1, there was a small number of CD4(+)IL-17(+) T cells and a large number of CD4(+)IL-10(+) and CD4(+)CD25(+)Foxp3(+) T cells in the IL-35 group. Most importantly, we found that IL-35 decreased the total number of macrophages and ratio of M1/M2 macrophages, which has not been reported previously. In addition, compared with dexamethasone, IL-35 showed long-term therapeutic efficacy. In summary, our results strongly indicate that IL-35 plays a potent immunosuppressive role in psoriasis. Thus, IL-35 has potential for development as a new therapeutic strategy for patients with chronic psoriasis and other cutaneous inflammatory diseases.
AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model.
Cochez Perrine M,Michiels Camille,Hendrickx Emilie,Van Belle Astrid B,Lemaire Muriel M,Dauguet Nicolas,Warnier Guy,de Heusch Magali,Togbe Dieudonnée,Ryffel Bernhard,Coulie Pierre G,Renauld Jean-Christophe,Dumoutier Laure
European journal of immunology
IL-22 has a detrimental role in skin inflammatory processes, for example in psoriasis. As transcription factor, AhR controls the IL-22 production by several cell types (i.e. Th17 cells). Here, we analyzed the role of Ahr in IL-22 production by immune cells in the inflamed skin, using an imiquimod-induced psoriasis mouse model. Our results indicate that IL-22 is expressed in the ear of imiquimod-treated Ahr(-/-) mice but less than in wild-type mice. We then studied the role of AhR on three cell populations known to produce IL-22 in the skin: γδ T cells, Th17 cells, and ILC3, and a novel IL-22-producing cell type identified in this setting: CD4(-) CD8(-) TCRβ(+) T cells. We showed that AhR is required for IL-22 production by Th17, but not by the three other cell types, in the imiquimod-treated ears. Moreover, AhR has a role in the recruitment of γδ T cells, ILC3, and CD4(-) CD8(-) TCRβ(+) T cells into the inflamed skin or in their local proliferation. Taken together, AhR has a direct role in IL-22 production by Th17 cells in the mouse ear skin, but not by γδ T cells, CD4(-) CD8(-) TCRβ(+) T cells and ILCs.
CXCL17 Attenuates Imiquimod-Induced Psoriasis-like Skin Inflammation by Recruiting Myeloid-Derived Suppressor Cells and Regulatory T Cells.
Oka Tomonori,Sugaya Makoto,Takahashi Naomi,Takahashi Takehiro,Shibata Sayaka,Miyagaki Tomomitsu,Asano Yoshihide,Sato Shinichi
Journal of immunology (Baltimore, Md. : 1950)
CXCL17 is expressed in a variety of cancers and promotes tumor progression by recruiting myeloid-derived suppressor cells (MDSCs). MDSCs suppress tumor immunity by attracting regulatory T cells (Tregs) into tumor sites through CCL5. In this study, we examined the role of CXCL17 in skin disorders. CXCL17 mRNA levels in psoriasis skin, but not in lesional skin of atopic dermatitis or cutaneous T cell lymphoma, were significantly higher than those in normal skin. CXCL17 was mainly expressed in the epidermis, and IFN-γ dose-dependently increased CXCL17 expression by human keratinocytes in vitro. As CXCL17 mRNA expression was increased by treatment with imiquimod (IMQ), we examined the effects of CXCL17 in IMQ-induced psoriasis-like skin inflammation. Injection of recombinant CXCL17 into the ear before and during IMQ application decreased ear thickness, inflammatory cytokine expression, and the number of infiltrating cells compared with PBS injection. Flow cytometric analysis and immunofluorescent staining revealed that the numbers of MDSCs, which are CD11bGr-1, and that of Tregs, which are CD4CD25, were higher in the ear of the CXCL17-injected mice than in PBS-injected mice. MDSCs, but not Tregs, showed chemotaxis to CXCL17 in vitro. When mice were injected with anti-CCL5 Ab or anti-CCL4 Ab simultaneously with recombinant CXCL17, ear thickness and cytokine expression increased to a similar level of mice treated with PBS and control IgG, suggesting that these chemokines were important for anti-inflammatory effects. Taken together, CXCL17 attenuates IMQ-induced psoriasis-like skin inflammation by recruiting MDSCs and Tregs, which may be important for regulating excessive inflammation in psoriasis skin.
Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk.
Shao Shuai,Fang Hui,Dang Erle,Xue Ke,Zhang Jieyu,Li Bing,Qiao Hongjiang,Cao Tianyu,Zhuang Yuchen,Shen Shengxian,Zhang Tongmei,Qiao Pei,Li Caixia,Gudjonsson Johann E,Wang Gang
Frontiers in immunology
Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis.
IL-21 Induces an Imbalance of Th17/Treg Cells in Moderate-to-Severe Plaque Psoriasis Patients.
Shi Yuling,Chen Zeyu,Zhao Zihan,Yu Yingyuan,Fan Huayu,Xu Xiaoguang,Bu Xiaolin,Gu Jun
Frontiers in immunology
Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4 T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood. IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4 T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis. IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4 T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients. Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations.
Integrated computational approach to the analysis of RNA-seq data reveals new transcriptional regulators of psoriasis.
Zolotarenko Alena,Chekalin Evgeny,Mesentsev Alexandre,Kiseleva Ludmila,Gribanova Elena,Mehta Rohini,Baranova Ancha,Tatarinova Tatiana V,Piruzian Eleonora S,Bruskin Sergey
Experimental & molecular medicine
Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3-) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions.
Inhibition of sphingosine 1-phosphate lyase activates human keratinocyte differentiation and attenuates psoriasis in mice.
Jeon Suwon,Song Jaehwi,Lee Dongyup,Kim Goon-Tae,Park Si-Hyun,Shin Dong-Yoon,Shin Kyong-Oh,Park Kyungho,Shim Soon-Mi,Park Tae-Sik
Journal of lipid research
Sphingosine 1-phosphate (S1P) lyase is an intracellular enzyme that catalyzes the irreversible degradation of S1P and has been suggested as a therapeutic target for the treatment of psoriasis vulgaris. Because S1P induces differentiation of keratinocytes, we examined whether modulation of S1P lyase and altered intracellular S1P levels regulate proliferation and differentiation of human neonatal epidermal keratinocyte (HEKn) cells. To identify the physiological functions of S1P lyase in skin, we inhibited S1P lyase in HEKn cells with an S1P lyase-specific inhibitor (SLI) and with S1P lyase 1 (SGPL1)-specific siRNA (siSGPL1). In HEKn cells, pharmacological treatment with the SLI caused G1 arrest by upregulation of p21 and p27 and induced keratin 1, an early differentiation marker. Similarly, genetic suppression by siSGPL1 arrested the cell cycle at the G1 phase and activated differentiation. In addition, enzyme suppression by siSGPL1 upregulated keratin 1 and differentiation markers including involucrin and loricrin. When hyperproliferation of HEKn cells was induced by interleukin (IL)-17 and IL-22, pharmacologic inhibition of S1P lyase by SLI decreased proliferation and activated differentiation of HEKn cells simultaneously. In addition, SLI administration ameliorated imiquimod-induced psoriatic symptoms including erythema, scaling, and epidermal thickness in vivo. We thus demonstrated that S1P lyase inhibition reduces cell proliferation and induces keratinocyte differentiation, and that inhibition may attenuate psoriasiform changes. Collectively, these findings suggest that S1P lyase is a modulating factor for proliferation and differentiation, and support its potential as a therapeutic target for psoriasis in human keratinocytes.
miR-340 Alleviates Psoriasis in Mice through Direct Targeting of IL-17A.
Bian Jiang,Liu Ruiling,Fan Tingting,Liao Lijuan,Wang Shaowen,Geng Wenwen,Wang Ting,Shi Weiyun,Ruan Qingguo
Journal of immunology (Baltimore, Md. : 1950)
Th17 cell is a well-known lineage of CD4 effector Th cells that selectively produce IL-17A and play critical roles during the pathogenesis of autoimmune disease. A microRNA (miRNA) is a small noncoding RNA molecule that functions in posttranscriptional regulation of gene expression. Recently, an increasing number of studies have demonstrated that multiple miRNAs are dysregulated in patients with various autoimmune diseases and mediate autoimmune disease pathologic condition at least in part through the regulation of Th17 response. However, among the few miRNAs identified so far that play possible roles in the differentiation of Th17 cells, they all regulate the Th17 response through targeting negative or positive regulators of Th17 differentiation. In the current study, we sought to identify new miRNAs that can directly regulate the expression of IL-17A, the most important cytokine produced by Th17 cells. Our results showed that the 3' untranslated region of mouse IL-17A can act as a negative regulatory element to downregulate gene expression. Further study revealed that miR-340 can specifically bind to the 3' untranslated region of mouse IL-17A and downregulate the expression of endogenous IL-17A. More importantly, we demonstrated that treatment with miR-340 alleviates the clinical severity of imiquimod-induced psoriasis in mice through the downregulation of IL-17A. These data indicate that miR-340 may be a useful therapeutic target for the treatment of psoriasis and other IL-17A-mediated autoimmune diseases.
Dermal mesenchymal stem cells: a resource of migration-associated function in psoriasis?
Niu Xuping,Li Junqing,Zhao Xincheng,Wang Qiang,Wang Gang,Hou Ruixia,Li Xinhua,An Peng,Yin Guohua,Zhang Kaiming
Stem cell research & therapy
BACKGROUND:Psoriasis is a chronic and systemic, immune-mediated, inflammatory disease. Mesenchymal stem cells have effects on the inflammatory microenvironment, including regulating the proliferation, differentiation, recruitment, and migration of immunocytes. METHODS:To investigate whether dermal mesenchymal stem cells (DMSCs) may act on migration of immunocytes in psoriasis patients, 22 patients with psoriasis and 22 matching healthy controls (age and sex in this study) were recruited. Seven migration-associated genes including chemokine like receptor-1 (CMKLR-1), collagen type VIII alpha1 (COL8A-1), neuropilin and tolloid-like 2 (NETO-2), nik-related kinase (NRK), secreted frizzled-related protein (SFRP), sulfate 6-O-endosulfatase 2 (SULF-2), and synaptotagmin-like protein 2 (SYTL-2) were analyzed by quantitative real-time reverse transcription PCR and western blot. Peripheral blood-derived mononuclear cells (PBMCs) migration to MSCs was measured using a Thanswell chamber system. RESULTS:We observed the upregulation of CMKLR-1, COL8A-1, NETO-2, NRK, SYTL-2, and SULF-2 in dermal mesenchymal stem cells derived from patients with psoriasis at both mRNA and protein level, however, a significant downregulation of SFRP-2 between two groups. By contrast, there were no significant between-group differences at the mRNA and protein expression level of NETO-2 and SULF-2. The migration assay showed that in vitro the normal PBMC migration to psoriatic DMSC group was a 6.3 ± 0.7-fold increase compared with the control group. CONCLUSIONS:The results may suggest a potential pathogenetic involvement of DMSCs on migration of monocytes in psoriasis. Immune responses are regulated at the level of DMSCs, which probably represent the cells primarily involved in the "psoriatic march."
PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis.
Martini Silvia,Pozzi Giulia,Carubbi Cecilia,Masselli Elena,Galli Daniela,Di Nuzzo Sergio,Banchini Antonio,Gobbi Giuliana,Vitale Marco,Mirandola Prisco
European journal of immunology
PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4 -T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune-mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4 -T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4 subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4 -T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4 -T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17-lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17-mediated diseases.
The Macrophage Mannose Receptor Regulate Mannan-Induced Psoriasis, Psoriatic Arthritis, and Rheumatoid Arthritis-Like Disease Models.
Hagert Cecilia,Sareila Outi,Kelkka Tiina,Jalkanen Sirpa,Holmdahl Rikard
Frontiers in immunology
The injection of mannan into mice can result in the development of psoriasis (Ps) and psoriatic arthritis (PsA), whereas co-injection with antibodies toward collagen type II leads to a chronic rheumatoid-like arthritis. The critical event in all these diseases is mannan-mediated activation of macrophages, causing more severe disease if the macrophages are deficient in neutrophil cytosolic factor 1 (Ncf1), i.e., lack the capacity to make a reactive oxygen species (ROS) burst. In this study, we investigated the role of one of the receptors binding mannan; the macrophage mannose receptor (MR, CD206). MR is a C-type lectin present on myeloid cells and lymphatics. We found that mice deficient in MR expression had more severe mannan-induced Ps, PsA as well as rheumatoid-like arthritis. Interestingly, the MR-mediated protection was partly lost in mutated mice and was associated with an type 2 macrophage expansion. In conclusion, these results show that MR protects against a pathogenic inflammatory macrophage response induced by mannan and is associated with induction of ROS.
Transcription Factor Retinoid-Related Orphan Receptor γt: A Promising Target for the Treatment of Psoriasis.
Tang Lipeng,Yang Xiaozhi,Liang Yongxin,Xie Hesong,Dai Zhenhua,Zheng Guangjuan
Frontiers in immunology
Psoriasis, which is a common chronic inflammatory skin disease, endangers human health and brings about a major economic burden worldwide. To date, treatments for psoriasis remain unsatisfied because of their clinical limitations and various side effects. Thus, developing a safer and more effective therapy for psoriasis is compelling. Previous studies have explicitly shown that psoriasis is an autoimmune disease that is predominantly mediated by T helper 17 (Th17) cells, which express high levels of interleukin-17 (IL-17) in response to interleukin-23 (IL-23). The discovery of the IL-23-Th17-IL-17 axis in the development of psoriasis has led to the paradigm shift of understanding pathogenesis of psoriasis. Although anti-IL-17 antibodies show marked clinical efficacy in treating psoriasis, compared with antibodies targeting IL-17A or IL-17R alone, targeting Th17 cells themselves may have a maximal benefit by affecting multiple proinflammatory cytokines, including IL-17A, IL-17F, IL-22, and granulocyte-macrophage colony-stimulating factor, which likely act synergistically to drive skin inflammation in psoriasis. In this review, we mainly focus on the critical role of Th17 cells in the pathogenesis of psoriasis. Especially, we explore the small molecules that target retinoid-related orphan receptor γt (RORγt), a vital transcription factor for Th17 cells. Given that RORγt is the lineage-defining transcription factor for Th17 cell differentiation, targeting RORγt small molecular inverse agonists may be a promising strategy for the treatment of Th17-mediated psoriasis.
Protein biomarker for psoriasis: A systematic review on their role in the pathomechanism, diagnosis, potential targets and treatment of psoriasis.
Yadav Krishna,Singh Deependra,Singh Manju Rawat
International journal of biological macromolecules
Psoriasis is defined as a long-lasting multifactorial inflammatory autoimmune skin condition precisely characterized by delimited, erythematic papules with adherent shiny scales. The conditions are led by hyperproliferative responses of epidermis due to hyperactivation and immature keratinocytes production. The psoriatic skin consists of the thickened epidermal layer, in concurrence with inflammatory exudates in the dermis mainly of dendritic cells, neutrophils, T cells, and macrophages, contributing to the distinct manifestation of psoriatic lesions. It consents to multifaceted and discrete pathology due to the genetic and immunological alteration resulting from abnormal expression of various regulatory and structural proteins. These proteins are associated with various cellular and sub-cellular activities. Therefore, the presence of protein in a pathological cellular environment in the psoriatic lesions as well as in serum could be a great avenue for the insight of pathomechanism, anticipation and diagnosis of psoriasis. Research of protein biomarker in psoriasis is yet a developing realm to be explored by both fundamental and clinical researchers. This review is an attempt to assimilate the current discoveries and revelations of different proteins as a biomarker and their importance in pathogenesis, diagnosis, treatment, and anticipation of both the inflammatory and other dermatological aspects of psoriasis.
The Interplay Between Keratinocytes and Immune Cells in the Pathogenesis of Psoriasis.
Albanesi Cristina,Madonna Stefania,Gisondi Paolo,Girolomoni Giampiero
Frontiers in immunology
Psoriasis is a chronic inflammatory skin disease resulting from genetic, epigenetic, environmental, and lifestyle factors. To date, several immunopathogenic mechanisms of psoriasis have been elucidated, and, in the current model, the cross talk between autoreactive T cells and resident keratinocytes generates inflammatory and immune circuits responsible for the initiation, progression, and persistence of the disease. Several autoantigens derived from keratinocytes (i.e., LL37 cathelecidin/nucleic acid complexes, newly generated lipid antigens) have been identified, which may trigger initial activation of T cells, particularly IL-17-producing T cells, T helper (Th)1 and Th22 cells. Hence, lymphokines released in skin lesions are pivotal for keratinocyte activation and production of inflammatory molecules, which in turn lead to amplification of the local immune responses. Intrinsic genetic alterations of keratinocytes in the activation of signal transduction pathways dependent on T-cell-derived cytokines are also fundamental. The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.
Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4Foxp3 Regulatory T Cells.
Chen Yuchao,Zhang Qunfang,Liu Huazhen,Lu Chuanjian,Liang Chun-Ling,Qiu Feifei,Han Ling,Dai Zhenhua
Frontiers in immunology
Psoriasis is an autoimmune and inflammatory skin disease affecting around 2-3% of the world's population. Patients with psoriasis need extensive treatments with global immunosuppressive agents that may cause severe side effects. Esculetin, a type of coumarins, is an active ingredient extracted mainly from the bark of Fraxinus rhynchophylla, which has been used to treat inflammatory and autoimmune diseases in China. However, the antipsoriatic effects of esculetin have not been reported. In this study, we aimed to investigate the effects of esculetin on psoriatic skin inflammation in a mouse model and explored the potential molecular mechanisms underlying its action. We found that esculetin ameliorated the skin lesion and reduced PASI scores as well as weight loss in imiquimod-induced psoriasis-like mice, accompanied with weakened proliferation and differentiation of keratinocytes and T cell infiltration in esculetin-treated psoriatic mice. In addition, esculetin reduced the frequency of CD8CD44CD62L effector T cells in psoriatic mice. In contrast, it increased the frequency of CD4Foxp3 Tregs in both lymph nodes and spleens of the psoriatic mice while promoting the differentiation of CD4CD25 T cells into CD4Foxp3 Tregs . Interestingly, depleting CD4Foxp3 Tregs largely reversed esculetin-mediated reduction in PASI scores, indicating that esculetin attenuates murine psoriasis mainly by inducing CD4Foxp3 Tregs. Furthermore, the mRNA levels of proinflammatory cytokines in the psoriatic mouse skin, including IL-6, IL-17A, IL-22, IL-23, TNF-α, and IFN-γ, were dramatically decreased by the treatment with esculetin. Finally, we found that esculetin inhibited the phosphorylation of IKKα and P65 in the psoriatic skin, suggesting that it inhibits the activation of NF-κB signaling. Thus, we have demonstrated that esculetin attenuates psoriasis-like skin lesion in mice and may be a potential therapeutic candidate for the treatment of psoriasis in clinic.
Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress.
Chimenti Maria Sole,Sunzini Flavia,Fiorucci Laura,Botti Elisabetta,Fonti Giulia Lavinia,Conigliaro Paola,Triggianese Paola,Costa Luisa,Caso Francesco,Giunta Alessandro,Esposito Maria,Bianchi Luca,Santucci Roberto,Perricone Roberto
Frontiers in immunology
Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.
Epidermal mTORC1 Signaling Contributes to the Pathogenesis of Psoriasis and Could Serve as a Therapeutic Target.
Frontiers in immunology
Although modern biologics targeting different inflammatory mediators show promising therapeutic success, comprehensive knowledge about the molecular events in psoriatic keratinocytes that contribute to the pathogenesis and could serve as therapeutic targets is still scarce. However, recent efforts to understand the deregulated signal transduction pathways have led to the development of small molecule inhibitors e.g., tofacitinib targeting the Jak/Stat cascade that opens additional therapeutic options. Recently, the PI3-K/Akt/mTOR signaling pathway has emerged as an important player in the control of epidermal homeostasis. This review summarizes the current knowledge on the role of this pathway in the pathogenesis of psoriasis, especially the epidermal manifestation of the disease and discusses current approaches to target the pathway therapeutically.
Rhododendrin inhibits toll-like receptor-7-mediated psoriasis-like skin inflammation in mice.
Jeon Yoon-Jae,Sah Shyam Kishor,Yang Hee Seung,Lee Ji Hae,Shin Jongheon,Kim Tae-Yoon
Experimental & molecular medicine
Many active compounds present in Rhododendron brachycarpum have been used in traditional Oriental medicine for the treatment of various skin diseases. However, the precise mechanism of action of the compounds isolated from R. brachycarpum and their relevance as therapeutics for the treatment of psoriasis remain elusive. In this study, we report that rhododendrin isolated from R. brachycarpum strongly inhibits imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. We showed that topical treatment with rhododendrin reduces IMQ-induced skin hyperplasia, inflammatory mononuclear cell infiltration and the expression of pro-inflammatory mediators in mouse skin. In addition, we found that rhododendrin inhibits the activation of the TLR-7/NF-κB and mitogen-activated protein kinase pathways in both IMQ-induced psoriasis-like skin inflammation in mice and in normal human epidermal keratinocytes treated with IMQ. These results suggest that rhododendrin has an anti-inflammatory effect and can be used as a therapeutic to fight against psoriasis and other inflammatory skin diseases.
Essential Role of CARD14 in Murine Experimental Psoriasis.
Tanaka Mayuri,Kobiyama Kouji,Honda Tetsuya,Uchio-Yamada Kozue,Natsume-Kitatani Yayoi,Mizuguchi Kenji,Kabashima Kenji,Ishii Ken J
Journal of immunology (Baltimore, Md. : 1950)
Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in mice. Comparison of the early gene signature of the skin between IMQ-cream-treated mice and mice revealed not only their similarity, but also distinct gene sets targeted by IL-23. Cell type-specific analysis of these mice identified skin Langerin Langerhans cells as a potent producer of IL-23, which was dependent on both TLR7 and TLR9 but independent of CARD14, suggesting that CARD14 is acting downstream of IL-23, not TLR7 or TLR9. Instead, a bone marrow chimera study suggested that CARD14 in radio-sensitive hematopoietic cells was required for IMQ-induced psoriasiform skin inflammation, controlling the number of Vγ4 T cells producing IL-17 or IL-22 infiltrating through the dermis to the inflamed epidermis. These data indicate that CARD14 is essential and a potential therapeutic target for psoriasis.
Bcl-3 induced by IL-22 via STAT3 activation acts as a potentiator of psoriasis-related gene expression in epidermal keratinocytes.
Tohyama Mikiko,Shirakata Yuji,Hanakawa Yasushi,Dai Xiuju,Shiraishi Ken,Murakami Masamoto,Miyawaki Saori,Mori Hideki,Utsunomiya Ryo,Masuda Kana,Hashimoto Koji,Sayama Koji
European journal of immunology
IL-22 induces STAT3 phosphorylation and mediates psoriasis-related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl-3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL-22 increased Bcl-3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human β-defensin 2 mRNA expression caused by IL-22 were abolished by siRNA against Bcl-3. Although CCL20 expression was also augmented by IL-22, the knockdown of Bcl-3 increased its level. Moreover, the combination of IL-22 and IL-17A enhanced Bcl-3 production, IL-22-induced gene expression, and the expression of other psoriasis-related genes, including those encoding IL-17C, IL-19, and IL-36γ. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl-3. Bcl-3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl-3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl-3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL-22-STAT3-Bcl-3 pathway may be important in the pathogenesis of psoriasis.
PSORI-CM02 Formula Increases CD4+ Foxp3+ Regulatory T Cell Frequency and Ameliorates Imiquimod-Induced Psoriasis in Mice.
Chen Haiming,Liu Huazhen,Lu Chuanjian,Wang Maojie,Li Xiong,Zhao Hui,Yan Yuhong,Yu Wanling,Han Ling,Dai Zhenhua
Frontiers in immunology
Psoriasis is an autoimmune and inflammatory disease, which is estimated to affect 2-3% of the population in the world. PSORI-CM02 is an empirical formula of Chinese medicine optimized from Yin Xie Ling, which is widely used to treat psoriasis in China for decades. However, its antipsoriatic mechanisms are still not well understood. Here, we explored the therapeutic effects of PSORI-CM02 on psoriasis and its mechanisms of action in imiquimod-induced psoriasis-like mouse models and human HaCaT cells. In experiments , PSORI-CM02 significantly inhibited HaCaT cell proliferation in dose-dependent and time-dependent manners. Furthermore, it hindered the progression of HaCaT cell cycle and arrested HaCaT cells at G1 phase. On the other hand, our studies demonstrated that PSORI-CM02 dramatically reduced psoriasis area and severity index scores and lesion temperature in imiquimod-induced psoriatic mice. The antioxidative activities of glutathione, catalase, and superoxide dismutase were increased while oxidative activity of malonaldehyde was markedly decreased after treatments with PSORI-CM02. PSORI-CM02 also suppressed the mRNA expression of proinflammatory cytokines, including TNF-α, IL-6, and IL-17, and lowered their protein levels in the serum as well. In addition, PSORI-CM02 could reduce the expression of IKKα and NF-κB in psoriatic skin tissue. It also upregulated the proportion of CD4+ Foxp3+ regulatory T cells (Tregs) in both lymph nodes and spleens and promoted CD4+ CD25+ Treg proliferation . Taken together, our research demonstrated that PSORI-CM02 inhibited HaCaT cell proliferation by arresting them at G1 phase and alleviated systemic inflammation and psoriasis in mice altering the oxidative/anti-oxidative status, tipping the balance between Th17 responsiveness and CD4+ Foxp3+ Treg generation, and suppressing the expression of proinflammatory cytokines as well as NF-κB signaling.
Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function.
Ippagunta Sirish K,Gangwar Ruchika,Finkelstein David,Vogel Peter,Pelletier Stephane,Gingras Sebastien,Redecke Vanessa,Häcker Hans
Proceedings of the National Academy of Sciences of the United States of America
Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17-induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.
Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ.
Ainscough Joseph S,Macleod Tom,McGonagle Dennis,Brakefield Rosella,Baron Jens M,Alase Ade,Wittmann Miriam,Stacey Martin
Proceedings of the National Academy of Sciences of the United States of America
The proinflammatory cytokine IL-36γ is highly expressed in epithelial cells and is a pivotal mediator of epithelial inflammation. In particular, IL-36γ is strongly associated with the inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36γ is expressed as an inactive precursor and must be processed by specific proteases to become bioactive. Our aim therefore was to identify protease/s capable of IL-36γ activation and explore the importance of this activation in psoriasis. Using a keratinocyte-based activity assay in conjunction with small-molecule inhibitors and siRNA gene silencing, cathepsin S was identified as the major IL-36γ-activating protease expressed by epithelial cells. Interestingly, cathepsin S activity was strongly up-regulated in samples extracted from psoriasis patients relative to healthy controls. In addition, IL-36γ-Ser18, identified as the main product of cathepsin S-dependent IL-36γ cleavage, induced psoriasiform changes in human skin-equivalent models. Together, these data provide important mechanistic insights into the activation of IL-36γ and highlight that cathepsin S-mediated activation of IL-36γ may be important in the development of numerous IL-36γ-driven pathologies, in addition to psoriasis.
IκBζ is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes.
Müller Anne,Hennig André,Lorscheid Sebastian,Grondona Paula,Schulze-Osthoff Klaus,Hailfinger Stephan,Kramer Daniela
Proceedings of the National Academy of Sciences of the United States of America
Proinflammatory cytokine signaling in keratinocytes plays a crucial role in the pathogenesis of psoriasis, a skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although IL-17A and TNFα are effective therapeutic targets in psoriasis, IL-36 has recently emerged as a proinflammatory cytokine. However, little is known about IL-36 signaling and its downstream transcriptional responses. Here, we found that exposure of keratinocytes to IL-36 induced the expression of IκBζ, an atypical IκB member and a specific transcriptional regulator of selective NF-κB target genes. Induction of IκBζ by IL-36 was mediated by NF-κB and STAT3. In agreement, IL-36-mediated induction of IκBζ was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IκBζ-knockout mice were protected against IL-36-mediated dermatitis, accompanied by reduced proinflammatory gene expression, decreased immune cell infiltration, and a lack of keratinocyte hyperproliferation. Moreover, expression of IκBζ mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with levels. Thus our results uncover an important role for IκBζ in IL-36 signaling and validate IκBζ as an attractive target for psoriasis therapy.
Brief Report: CXCL10 Is a Possible Biomarker for the Development of Psoriatic Arthritis Among Patients With Psoriasis.
Abji Fatima,Pollock Remy A,Liang Kun,Chandran Vinod,Gladman Dafna D
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Biomarkers that can predict the development of psoriatic arthritis (PsA) in patients with psoriasis would be useful in clinical practice. The aim of this study was to assess whether CXCL10 could be a predictive biomarker of PsA prior to its onset. METHODS:Psoriasis patients without arthritis were followed up prospectively and assessed annually for development of PsA by a rheumatologist. Patients in whom PsA developed were designated as converters, while those in whom PsA did not develop were termed nonconverters. Baseline serum concentrations of CXCL10 were measured by Luminex assay in 46 converters and 45 nonconverters. RESULTS:The level of CXCL10 was significantly higher in converters (median 493 pg/ml [interquartile range (IQR) 356-984]) than in nonconverters (median 371 pg/ml [IQR 263-578]; P = 0.005). In contrast, C-reactive protein (CRP) levels were not significantly different between converters and nonconverters at baseline. CXCL10 was associated with conversion status after adjustment for age, sex, duration of psoriasis, and duration of follow-up (odds ratio 1.3, 95% confidence interval 1.1-1.5, P = 0.004). In a subset of converters, the CXCL10 level was significantly higher at baseline (median 927.4 pg/ml [IQR 547.6-1,243]) than after PsA diagnosis (491.5 pg/ml [IQR 323.2-607]; P < 0.0001), while CRP levels were lower at baseline (26.6 μg/ml [IQR 16.37-62.75]) than after PsA diagnosis (36.1 μg/ml [IQR 14.74-101.7]; P = 0.003). CXCL10 gene expression was increased 17.3-fold in synovial fluid (SF) compared with blood from PsA patients (P = 0.01) and 44.3-fold in the SF of PsA patients compared with the SF of patients with gout (P = 0.001). CONCLUSION:CXCL10 may be involved in PsA pathogenesis and is a candidate predictive biomarker for PsA in patients with psoriasis.
Complementary and Alternative Medicine Therapies for Psoriasis: A Systematic Review.
Gamret A Caresse,Price Alexandra,Fertig Raymond M,Lev-Tov Hadar,Nichols Anna J
Importance:Up to 51% of patients with psoriasis report the use of complementary and alternative medicine (CAM) in their treatment regimen, although it is unclear which CAM therapies are effective for treatment of psoriasis. Objective:This review compiles the evidence on the efficacy of the most studied CAM modalities for treatment of patients with plaque psoriasis and discusses those therapies with the most robust available evidence. Evidence Review:PubMed, Embase, and ClinicalTrials.gov searches (1950-2017) were used to identify all documented CAM psoriasis interventions in the literature. The criteria were further refined to focus on those treatments identified in the first step that had the highest level of evidence for plaque psoriasis with more than 1 randomized clinical trial supporting their use. This excluded therapies lacking randomized clinical trial (RCT) data or showing consistent inefficacy. Findings:Primary CAM therapy searches identified 457 articles, of which 107 articles were retrieved for closer examination. Of those articles, 54 were excluded because the CAM therapy did not have more than 1 RCT on the subject or showed consistent lack of efficacy. An additional 7 articles were found using references of the included studies, resulting in a total of 44 RCTs (17 double-blind, 13 single-blind, and 14 nonblind), 10 uncontrolled trials, 2 open-label nonrandomized controlled trials, 1 prospective controlled trial, and 3 meta-analyses. Compared with placebo, application of topical indigo naturalis, studied in 5 RCTs with 215 participants, showed significant improvements in the treatment of psoriasis. Treatment with curcumin, examined in 3 RCTs (with a total of 118 participants), 1 nonrandomized controlled study, and 1 uncontrolled study, conferred statistically and clinically significant improvements in psoriasis plaques. Fish oil treatment was evaluated in 20 studies (12 RCTs, 1 open-label nonrandomized controlled trial, and 7 uncontrolled studies); most of the RCTs showed no significant improvement in psoriasis, whereas most of the uncontrolled studies showed benefit when fish oil was used daily. Meditation and guided imagery therapies were studied in 3 single-blind RCTs (with a total of 112 patients) and showed modest efficacy in treatment of psoriasis. One meta-analysis of 13 RCTs examined the association of acupuncture with improvement in psoriasis and showed significant improvement with acupuncture compared with placebo. Conclusions and Relevance:The CAM therapies with the most robust evidence of efficacy for treatment of psoriasis are indigo naturalis, curcumin, dietary modification, fish oil, meditation, and acupuncture. This review will aid practitioners in advising patients seeking unconventional approaches for treatment of psoriasis.
IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis.
Hou Yuzhu,Zhu Linnan,Tian Hongling,Sun Hai-Xi,Wang Ruoyu,Zhang Lianfeng,Zhao Yong
Protein & cell
Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis.
Decrease of galectin-3 in keratinocytes: A potential diagnostic marker and a critical contributor to the pathogenesis of psoriasis.
Shi Zhen-Rui,Tan Guo-Zhen,Cao Cui-Xiang,Han Yan-Fang,Meng Zhen,Man Xiao-Yong,Jiang Ze-Xin,Zhang Yu-Ping,Dang Ning-Ning,Wei Kai-Hua,Bu Ding-Fang,Liu Fu-Tong,Wang Liangchun
Journal of autoimmunity
Psoriasis-specific proteins dysregulated in keratinocytes and involved in the pathophysiological process of psoriasis remains elusive. We report here that epidermal galectin-3 expression is significantly downregulated in lesional skin, but not in non-lesional skin in psoriasis patients, nor in a group of diseases known as psoriasiform dermatitis clinically and histologically similar to psoriasis. The deficiency of epidermal galectin-3 is sufficient to promote development of psoriatic lesions, as evidenced by more severe skin inflammation in galectin-3 knockout (gal3) mice, compared to wild-type mice, after imiquimod treatment, and in skin from gal3 mice grafted onto wildtype mice. The development of psoriatic-like lesions is attributable to 1) the spontaneously tuning up of psoriasis signatures in keratinocytes through JNK pathway; and 2) neutrophil accumulation caused by the enhanced leukocyte-recruiting capacity associated with overexpression of S100A7-9 and CXCL-1, 8 in keratinocytes with impaired galectin-3 expression. Psoriasis-like skin inflammation is significantly improved in gal-3 mice both by inhibition of neutrophils accumulation with a selective CXCR2 antagonist of SB225002, and by intracutaneous injection of recombinant galectin-3. Overall, these findings offer promising galectin-3-related diagnostic and therapeutic resolutions of psoriasis.
Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis.
Bachelez Hervé,Choon Siew-Eng,Marrakchi Slaheddine,Burden A David,Tsai Tsen-Fang,Morita Akimichi,Turki Hamida,Hall David B,Shear Michael,Baum Patrick,Padula Steven J,Thoma Christian
The New England journal of medicine
GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis.
Joshi Aditya A,Lerman Joseph B,Aberra Tsion M,Afshar Mehdi,Teague Heather L,Rodante Justin A,Krishnamoorthy Parasuram,Ng Qimin,Aridi Tarek Z,Salahuddin Taufiq,Natarajan Balaji,Lockshin Benjamin N,Ahlman Mark A,Chen Marcus Y,Rader Daniel J,Reilly Muredach P,Remaley Alan T,Bluemke David A,Playford Martin P,Gelfand Joel M,Mehta Nehal N
RATIONALE:GlycA, an emerging inflammatory biomarker, predicted cardiovascular events in population-based studies. Psoriasis, an inflammatory disease associated with increased cardiovascular risk, provides a model to study inflammatory biomarkers in cardiovascular disease (CVD). Whether GlycA associates with psoriasis and how it predicts subclinical CVD beyond high-sensitivity C-reactive protein in psoriasis is unknown. OBJECTIVE:To investigate the relationships between GlycA and psoriasis and between GlycA and subclinical CVD. METHODS AND RESULTS:Patients with psoriasis and controls (n=412) participated in a 2-stage study. We measured GlycA by nuclear magnetic resonance spectroscopy. National Institutes of Health (NIH) participants underwent 18-F Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (18-FDG PET/CT) scans to assess vascular inflammation (VI) and coronary computed tomographic angiography to quantify coronary artery disease burden. Psoriasis cohorts were young (mean age=47.9), with low cardiovascular risk and moderate skin disease. high-sensitivity C-reactive protein and GlycA were increased in psoriasis compared with controls (GlycA: [PENN: 408.8±75.4 versus 289.4±60.2, P<0.0001; NIH: 415.8±63.2 versus 346.2±46, P<0.0001]) and demonstrated a dose-response with psoriasis severity. In stage 2, VI (β=0.36, P<0.001) and coronary artery disease (β=0.29, P=0.004) associated with GlycA beyond CV risk factors in psoriasis. In receiver operating characteristic analysis, GlycA added value in predicting VI (P=0.01) and coronary artery disease (P<0.01). Finally, initiating anti-tumor necrosis factor therapy (n=16) reduced psoriasis severity (P<0.001), GlycA (463.7±92.5 versus 370.1±78.5, P<0.001) and VI (1.93±0.36 versus 1.76±0.19, P<0.001), whereas GlycA remained associated with VI (β=0.56, P<0.001) post treatment. CONCLUSIONS:GlycA associated with psoriasis severity and subclinical CVD beyond traditional CV risk and high-sensitivity C-reactive protein. Moreover, psoriasis treatment reduced GlycA and VI. These findings support the potential use of GlycA in subclinical CVD risk assessment in psoriasis and potentially other inflammatory diseases.
The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases.
Harden Jamie L,Lewis Steven M,Lish Samantha R,Suárez-Fariñas Mayte,Gareau Daniel,Lentini Tim,Johnson-Huang Leanne M,Krueger James G,Lowes Michelle A
The Journal of allergy and clinical immunology
BACKGROUND:Many human diseases arise from or have pathogenic contributions from a dysregulated immune response. One pathway with immunomodulatory ability is the tryptophan metabolism pathway, which promotes immune suppression through the enzyme indoleamine 2,3-dioxygenase (IDO) and subsequent production of kynurenine. However, in patients with chronic inflammatory skin disease, such as psoriasis and atopic dermatitis (AD), another tryptophan metabolism enzyme downstream of IDO, L-kynureninase (KYNU), is heavily upregulated. The role of KYNU has not been explored in patients with these skin diseases or in general human immunology. OBJECTIVE:We sought to explore the expression and potential immunologic function of the tryptophan metabolism enzyme KYNU in inflammatory skin disease and its potential contribution to general human immunology. METHODS:Psoriatic skin biopsy specimens, as well as normal human skin, blood, and primary cells, were used to investigate the immunologic role of KYNU and tryptophan metabolites. RESULTS:Here we show that KYNU(+) cells, predominantly of myeloid origin, infiltrate psoriatic lesional skin. KYNU expression positively correlates with disease severity and inflammation and is reduced on successful treatment of psoriasis or AD. Tryptophan metabolites downstream of KYNU upregulate several cytokines, chemokines, and cell adhesions. By mining data on several human diseases, we found that in patients with cancer, IDO is preferentially upregulated compared with KYNU, whereas in patients with inflammatory diseases, such as AD, KYNU is preferentially upregulated compared with IDO. CONCLUSION:Our results suggest that tryptophan metabolism might dichotomously modulate immune responses, with KYNU as a switch between immunosuppressive versus inflammatory outcomes. Although tryptophan metabolism is increased in many human diseases, how tryptophan metabolism is proceeding might qualitatively affect the immune response in patients with that disease.
β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis.
Kolbinger Frank,Loesche Christian,Valentin Marie-Anne,Jiang Xiaoyu,Cheng Yi,Jarvis Philip,Peters Thomas,Calonder Claudio,Bruin Gerard,Polus Florine,Aigner Birgit,Lee David M,Bodenlenz Manfred,Sinner Frank,Pieber Thomas Rudolf,Patel Dhavalkumar D
The Journal of allergy and clinical immunology
BACKGROUND:IL-17A is a key driver of human autoimmune diseases, particularly psoriasis. OBJECTIVE:We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology. METHODS:We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases. RESULTS:IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P < .001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. β-Defensin 2 (BD-2) was identified as a biomarker of IL-17A-driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P < .0001; 2747 vs <218 pg/mL in dermis, P < .001), responsiveness to secukinumab therapy, and synergistic induction by IL-17A and TNF-α in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL-17A driven, we found that BD-2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD-2 levels correlated well with IL-17A levels (r = 0.70, n = 199, P < .001) and Psoriasis Area and Severity Index scores (r = 0.53, n = 281, P < .001). CONCLUSION:IL-17A is a primary driver of skin pathology in patients with psoriasis, and serum BD-2 is an easily measurable biomarker of IL-17A-driven skin pathology.
Tailored Therapist-Guided Internet-Based Cognitive Behavioral Treatment for Psoriasis: A Randomized Controlled Trial.
van Beugen Sylvia,Ferwerda Maaike,Spillekom-van Koulil Saskia,Smit Jurgen V,Zeeuwen-Franssen Manon E J,Kroft Elisabeth B M,de Jong Elke M G J,Otero Marisol E,Donders A Rogier T,van de Kerkhof Peter C M,van Middendorp Henriët,Evers Andrea W M
Psychotherapy and psychosomatics
OBJECTIVE:Patients with somatic conditions, such as psoriasis, frequently suffer from high burden of their disease in daily life and might benefit from internet-based cognitive behavioral therapy (ICBT) tailored to their adjustment problems. The aim of this multicenter randomized controlled trial was to examine the effects of therapist-guided, individually tailored ICBT in a clinical sample of patients with psoriasis. METHODS:A total of 131 patients with psoriasis, who were screened for a psychological risk profile, were randomized to either care as usual (CAU, n = 66) or ICBT in addition to CAU (n = 65). Participants filled out standardized self-report questionnaires assessing physical and psychological functioning and impact on daily activities at baseline, posttreatment assessment, and 6-month follow-up. RESULTS:In covariate-controlled linear mixed-model analyses, significantly larger improvements in ICBT compared to CAU were found in the primary outcomes physical functioning (p = 0.03, d = 0.36) and impact on daily activities (p = 0.04, d = 0.35), but not in psychological functioning (p = 0.32), up to 6 months after treatment compared to baseline. In explorative analyses, the working alliance measured at the beginning of ICBT treatment predicted improved physical (p = 0.02) and psychological (p < 0.001) outcomes. CONCLUSIONS:Results underline the promise of therapist-guided, individually tailored ICBT to improve physical functioning and reduce the impact of psoriasis on daily activities in patients with a psychological risk profile. Establishing a good therapeutic relationship early on may be an important factor that influences treatment outcomes in personalized ICBT interventions. Further research is needed to evaluate ICBT effectiveness in additional samples and to explore its underlying mechanisms.
Microbe-host interplay in atopic dermatitis and psoriasis.
Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers. We find that atopic dermatitis and psoriasis can be classified by distinct microbes, which differ from healthy volunteers microbiome composition. Atopic dermatitis is dominated by a single microbe (Staphylococcus aureus), and associated with a disease relevant host transcriptomic signature enriched for skin barrier function, tryptophan metabolism and immune activation. In contrast, psoriasis is characterized by co-occurring communities of microbes with weak associations with disease related gene expression. Our work provides a basis for biomarker discovery and targeted therapies in skin dysbiosis.
CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis.
Cibrian Danay,Saiz María Laura,de la Fuente Hortensia,Sánchez-Díaz Raquel,Moreno-Gonzalo Olga,Jorge Inmaculada,Ferrarini Alessia,Vázquez Jesús,Punzón Carmen,Fresno Manuel,Vicente-Manzanares Miguel,Daudén Esteban,Fernández-Salguero Pedro M,Martín Pilar,Sánchez-Madrid Francisco
The activation marker CD69 is expressed by skin γδ T cells. Here we found that CD69 controlled the aryl hydrocarbon receptor (AhR)-dependent secretion of interleukin 22 (IL-22) by γδ T cells, which contributed to the development of psoriasis induced by IL-23. CD69 associated with the aromatic-amino-acid-transporter complex LAT1-CD98 and regulated its surface expression and uptake of L-tryptophan (L-Trp) and the intracellular quantity of L-Trp-derived activators of AhR. In vivo administration of L-Trp, an inhibitor of AhR or IL-22 abrogated the differences between CD69-deficient mice and wild-type mice in skin inflammation. We also observed LAT1-mediated regulation of AhR activation and IL-22 secretion in circulating Vγ9(+) γδ T cells of psoriatic patients. Thus, CD69 serves as a key mediator of the pathogenesis of psoriasis by controlling LAT1-CD98-mediated metabolic cues.
Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting T17 cell polarization.
Tamehiro Norimasa,Nishida Kyoko,Sugita Yu,Hayakawa Kunihiro,Oda Hiroyo,Nitta Takeshi,Nakano Miwa,Nishioka Akiko,Yanobu-Takanashi Reiko,Goto Motohito,Okamura Tadashi,Adachi Reiko,Kondo Kazunari,Morita Akimichi,Suzuki Harumi
The Journal of allergy and clinical immunology
BACKGROUND:Ras homolog gene family H (RhoH) is a membrane-bound adaptor protein involved in proximal T-cell receptor signaling. Therefore RhoH plays critical roles in the differentiation of T cells; however, the function of RhoH in the effecter phase of the T-cell response has not been fully characterized. OBJECTIVE:We sought to explore the role of RhoH in inflammatory immune responses and investigated the involvement of RhoH in the pathogenesis of psoriasis. METHODS:We analyzed effector T-cell and systemic inflammation in wild-type and RhoH-null mice. RhoH expression in T cells in human PBMCs was quantified by using RT-PCR. RESULTS:RhoH deficiency in mice induced T17 polarization during effector T-cell differentiation, thereby inducing psoriasis-like chronic dermatitis. Ubiquitin protein ligase E3 component N-recognin 5 (Ubr5) and nuclear receptor subfamily 2 group F member 6 (Nr2f6) expression levels decreased in RhoH-deficient T cells, resulting in increased protein levels and DNA binding activity of retinoic acid-related orphan receptor γt. The consequential increase in IL-17 and IL-22 production induced T cells to differentiate into T17 cells. Furthermore, IL-22 binding protein/Fc chimeric protein reduced psoriatic inflammation in RhoH-deficient mice. Expression of RhoH in T cells was lower in patients with psoriasis with very severe symptoms. CONCLUSION:Our results indicate that RhoH inhibits T17 differentiation and thereby plays a role in the pathogenesis of psoriasis. Additionally, IL-22 binding protein has therapeutic potential for the treatment of psoriasis.
TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis.
Sidler Daniel,Wu Ping,Herro Rana,Claus Meike,Wolf Dennis,Kawakami Yuko,Kawakami Toshiaki,Burkly Linda,Croft Michael
Atopic dermatitis (AD) and psoriasis are driven by alternate type 2 and type 17 immune responses, but some proteins might be critical to both diseases. Here we show that a deficiency of the TNF superfamily molecule TWEAK (TNFSF12) in mice results in defective maintenance of AD-specific T helper type 2 (Th2) and psoriasis-specific Th17 cells in the skin, and impaired expression of disease-characteristic chemokines and cytokines, such as CCL17 and TSLP in AD, and CCL20 and IL-19 in psoriasis. The TWEAK receptor, Fn14, is upregulated in keratinocytes and dermal fibroblasts, and TWEAK induces these cytokines and chemokines alone and in synergy with the signature T helper cytokines of either disease, IL-13 and IL-17. Furthermore, subcutaneous injection of recombinant TWEAK into naive mice induces cutaneous inflammation with histological and molecular signs of both diseases. TWEAK is therefore a critical contributor to skin inflammation and a possible therapeutic target in AD and psoriasis.
Author Correction: Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.
Zuo Xianbo,Sun Liangdan,Yin Xianyong,Gao Jinping,Sheng Yujun,Xu Jinhua,Zhang Jianzhong,He Chundi,Qiu Ying,Wen Guangdong,Tian Hongqing,Zheng Xiaodong,Liu Shengxiu,Wang Wenjun,Li Weiran,Cheng Yuyan,Liu Longdan,Chang Yan,Wang Zaixing,Li Zenggang,Li Longnian,Wu Jianping,Fang Ling,Shen Changbing,Zhou Fusheng,Liang Bo,Chen Gang,Li Hui,Cui Yong,Xu Aie,Yang Xueqin,Hao Fei,Xu Limin,Fan Xing,Li Yuzhen,Wu Rina,Wang Xiuli,Liu Xiaoming,Zheng Min,Song Shunpeng,Ji Bihua,Fang Hong,Yu Jianbin,Sun Yongxin,Hui Yan,Zhang Furen,Yang Rongya,Yang Sen,Zhang Xuejun
This corrects the article DOI: 10.1038/ncomms7793.
Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis.
Huang Li-Hao,Zinselmeyer Bernd H,Chang Chih-Hao,Saunders Brian T,Elvington Andrew,Baba Osamu,Broekelmann Thomas J,Qi Lina,Rueve Joseph S,Swartz Melody A,Kim Brian S,Mecham Robert P,Wiig Helge,Thomas Michael J,Sorci-Thomas Mary G,Randolph Gwendalyn J
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4 T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.
MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation.
Wu Ruifang,Zeng Jinrong,Yuan Jin,Deng Xinjie,Huang Yi,Chen Lina,Zhang Peng,Feng Huan,Liu Zixin,Wang Zijun,Gao Xiaofei,Wu Haijing,Wang Honglin,Su Yuwen,Zhao Ming,Lu Qianjin
The Journal of clinical investigation
Immune imbalance of T lymphocyte subsets is a hallmark of psoriasis, but the molecular mechanisms underlying this aspect of psoriasis pathology are poorly understood. Here, we report that microRNA-210 (miR-210), a miR that is highly expressed in both psoriasis patients and mouse models, induces helper T (Th) 17 and Th1 cell differentiation but inhibits Th2 differentiation through repressing STAT6 and LYN expression, contributing to several aspects of the immune imbalance in psoriasis. Both miR-210 ablation in mice and inhibition of miR-210 by intradermal injection of antagomir-210 blocked the immune imbalance and the development of psoriasis-like inflammation in an imiquimod-induced or IL-23-induced psoriasis-like mouse model. We further showed that TGF-β and IL-23 enhance miR-210 expression by inducing HIF-1α, which recruits P300 and promotes histone H3 acetylation in the miR-210 promoter region. Our results reveal a crucial role for miR-210 in the immune imbalance of T lymphocyte subsets in psoriasis and suggest a potential therapeutic avenue.
Detection of IL-36γ through noninvasive tape stripping reliably discriminates psoriasis from atopic eczema.
Berekméri Anna,Latzko Anne,Alase Adewonuola,Macleod Tom,Ainscough Joseph S,Laws Philip,Goodfield Mark,Wright Andrew,Helliwell Philip,Edward Sara,Brown Gordon D,Reid Delyth M,Wenzel Joerg,Stacey Martin,Wittmann Miriam
The Journal of allergy and clinical immunology
Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis.
Zhang Zhuzhen,Zi Zhenzhen,Lee Eunice E,Zhao Jiawei,Contreras Diana C,South Andrew P,Abel E Dale,Chong Benjamin F,Vandergriff Travis,Hosler Gregory A,Scherer Philipp E,Mettlen Marcel,Rathmell Jeffrey C,DeBerardinis Ralph J,Wang Richard C
Proliferating cells, compared with quiescent cells, are more dependent on glucose for their growth. Although glucose transport in keratinocytes is mediated largely by the Glut1 facilitative transporter, we found that keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and homeostasis. Ex vivo metabolic profiling revealed altered sphingolipid, hexose, amino acid, and nucleotide metabolism in Glut1-deficient keratinocytes, thus suggesting metabolic adaptation. However, cultured Glut1-deficient keratinocytes displayed metabolic and oxidative stress and impaired proliferation. Similarly, Glut1 deficiency impaired in vivo keratinocyte proliferation and migration within wounded or UV-damaged mouse skin. Notably, both genetic and pharmacological Glut1 inactivation decreased hyperplasia in mouse models of psoriasis-like disease. Topical application of a Glut1 inhibitor also decreased inflammation in these models. Glut1 inhibition decreased the expression of pathology-associated genes in human psoriatic skin organoids. Thus, Glut1 is selectively required for injury- and inflammation-associated keratinocyte proliferation, and its inhibition offers a novel treatment strategy for psoriasis.
Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A.
Wang Mingchao,Zhang Shanshan,Zheng Guoxing,Huang Junjiu,Songyang Zhou,Zhao Xueqiang,Lin Xin
Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14 and Card14 mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14 mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors. Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-κB activation in keratinocytes in psoriatic initiation.
The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis.
Dainichi Teruki,Kitoh Akihiko,Otsuka Atsushi,Nakajima Saeko,Nomura Takashi,Kaplan Daniel H,Kabashima Kenji
The skin provides both a physical barrier and an immunologic barrier to external threats. The protective machinery of the skin has evolved to provide situation-specific responses to eliminate pathogens and to provide protection against physical dangers. Dysregulation of this machinery can give rise to the initiation and propagation of inflammatory loops in the epithelial microenvironment that result in inflammatory skin diseases in susceptible people. A defective barrier and microbial dysbiosis drive an interleukin 4 (IL-4) loop that underlies atopic dermatitis, while in psoriasis, disordered keratinocyte signaling and predisposition to type 17 responses drive a pathogenic IL-17 loop. Here we discuss the pathogenesis of atopic dermatitis and psoriasis in terms of the epithelial immune microenvironment-the microbiota, keratinocytes and sensory nerves-and the resulting inflammatory loops.
Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?
Baker Kenneth F,Isaacs John D
Annals of the rheumatic diseases
The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.