Strong renal expression of heat shock protein 70, high mobility group box 1, inducible nitric oxide synthase, and nitrotyrosine in mice model of severe malaria.
Fitri Loeki Enggar,Rosmarwati Ervina,Rizky Yesita,Budiarti Niniek,Samsu Nur,Mintaroem Karyono
Revista da Sociedade Brasileira de Medicina Tropical
INTRODUCTION:Renal damage is a consequence of severe malaria, and is generally caused by sequestration of Plasmodium falciparum -infected erythrocytes in the renal microcirculation, which leads to obstruction, hypoxia, and ischemia. This triggers high mobility group box 1 (HMGB1) to send a danger signal through toll-like receptors 2 and 4. This signal up-regulates inducible nitric oxide (iNOS) and nitrotyrosine to re-perfuse the tissue, and also increases heat shock protein 70 (HSP70) expression. As no study has examined the involvement of intracellular secondary molecules in this setting, the present study compared the renal expressions of HSP70, HMGB1, iNOS, and nitrotyrosine between mice suffered from severe malaria and normal mice. METHODS:C57BL/6 mice were divided into an infected group (intraperitoneal injection of 10 6 P. berghei ANKA) and a non-infected group. Renal damage was evaluated using hematoxylin eosin staining, and immunohistochemistry was used to evaluate the expressions of HSP70, HMGB1, iNOS, and nitrotyrosine. RESULTS:Significant inter-group differences were observed in the renal expressions of HSP70, HMGB1, and iNOS (p=0.000, Mann-Whitney test), as well as nitrotyrosine (p=0.000, independent t test). The expressions of HSP70 and HMGB1 were strongly correlated (p=0.000, R=1.000). No correlations were observed between iNOS and HMGB, HMGB1 and nitrotyrosine, HSP70 and nitrotyrosine, or iNOS and nitrotyrosine. CONCLUSIONS:It appears that HMGB1, HSP70, iNOS, and nitrotyrosine play roles in the renal damage that is observed in mice with severe malaria. Only HSP70 expression is strongly correlated with the expression of HMGB1.
10.1590/0037-8682-0049-2017
High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy.
Ravizza Teresa,Terrone Gaetano,Salamone Alessia,Frigerio Federica,Balosso Silvia,Antoine Daniel J,Vezzani Annamaria
Brain, behavior, and immunity
Approximately 30% of epilepsy patients experience seizures that are not controlled by the available drugs. Moreover, these drugs provide mainly a symptomatic treatment since they do not interfere with the disease's mechanisms. A mechanistic approach to the discovery of key pathogenic brain modifications causing seizure onset, recurrence and progression is instrumental for designing novel and rationale therapeutic interventions that could modify the disease course or prevent its development. In this regard, increasing evidence shows that neuroinflammation is a pathogenic factor in drug-resistant epilepsies. The High Mobility Group Box 1 (HMGB1)/Toll-like receptor 4 axis is a key initiator of neuroinflammation following brain injuries leading to epilepsy, and its activation contributes to seizure mechanisms in animal models. Recent findings have shown dynamic changes in HMGB1 and its isoforms in the brain and blood of animals exposed to acute brain injuries and undergoing epileptogenesis, and in surgically resected epileptic foci in humans. HMGB1 isoforms reflect different pathophysiological processes, and the disulfide isoform, which is generated in the brain during oxidative stress, is implicated in seizures, cell loss and cognitive dysfunctions. Interfering with disulfide HMGB1-activated cell signaling mediates significant therapeutic effects in epilepsy models. Moreover, both clinical and experimental data suggest that HMGB1 isoforms may serve as mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy. These novel findings suggest that the HMGB1 system could be targeted to prevent seizure generation and may provide clinically useful prognostic biomarkers which may also predict the patient's response to therapy.
10.1016/j.bbi.2017.10.008
High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches.
Paudel Yam Nath,Semple Bridgette D,Jones Nigel C,Othman Iekhsan,Shaikh Mohd Farooq
Journal of neurochemistry
Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti-epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high-mobility group box protein 1 (HMGB1), a DNA-binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1-targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.
10.1111/jnc.14663
Enlightening the role of high mobility group box 1 (HMGB1) in inflammation: Updates on receptor signalling.
Paudel Yam Nath,Angelopoulou Efthalia,Piperi Christina,Balasubramaniam Vinod R M T,Othman Iekhsan,Shaikh Mohd Farooq
European journal of pharmacology
High mobility group box 1 (HMGB1) is a ubiquitous protein, released passively by necrotic tissues or secreted actively by stressed cells. Extracellular HMGB1 is a typical damage-associated molecular pattern (DAMP) molecule which generates different redox types through binding with several receptors and signalling molecules, aggravating a range of cellular responses, including inflammation. HMGB1 is reported to participate in the pathogenesis of inflammatory diseases, through the interaction with pivotal transmembrane receptors, including the receptor for advanced glycation end products (RAGE) and toll-like receptor-4 (TLR-4). This review aims to highlight the role of HMGB1 in the innate inflammatory response describing its interaction with several cofactors and receptors that coordinate its downstream effects. Novel and underexplored HMGB1 binding molecules that have been actively involved in HMGB1-mediated inflammatory diseases/conditions with therapeutic potential are further discussed.
10.1016/j.ejphar.2019.172487
Impact of HMGB1, RAGE, and TLR4 in Alzheimer's Disease (AD): From Risk Factors to Therapeutic Targeting.
Paudel Yam Nath,Angelopoulou Efthalia,Piperi Christina,Othman Iekhsan,Aamir Khurram,Shaikh Mohd Farooq
Cells
Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.
10.3390/cells9020383
Targeting Inflammation Driven by HMGB1.
Frontiers in immunology
High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damage-associated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.
10.3389/fimmu.2020.00484
Toll-Like Receptor 4 (TLR4)/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility.
Zhang Peng,Yang Meirong,Chen Chunhua,Liu Liu,Wei Xinchuan,Zeng Si
Frontiers in immunology
Toll-like receptor 4 (TLR4) recognizes exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) and initiates the innate immune response. Opioid receptors (μ, δ, and κ) activate inhibitory G-proteins and relieve pain. This review summarizes the following types of TLR4/opioid receptor pathway crosstalk: (a) Opioid receptor agonists non-stereoselectively activate the TLR4 signaling pathway in the central nervous system (CNS), in the absence of lipopolysaccharide (LPS). Opioids bind to TLR4, in a manner parallel to LPS, activating TLR4 signaling, which leads to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression and the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. (b) Opioid receptor agonists inhibit the LPS-induced TLR4 signaling pathway in peripheral immune cells. Opioids operate as pro-inflammatory cytokines, resulting in neuroinflammation in the CNS, but they mediate immunosuppressive effects in the peripheral immune system. It is apparent that TLR4/opioid receptor pathway crosstalk varies dependent on the cell type and activating stimulus. (c) Both the TLR4 and opioid receptor pathways activate the mitogen-activated protein kinase (MAPK) pathway. This crosstalk is located downstream of the TLR4 and opioid receptor signaling pathways. Furthermore, the classic opioid receptor can also produce pro-inflammatory effects in the CNS via MAPK signaling and induce neuroinflammation. (d) Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions. This review also summarizes the potential effects of TLR4/opioid receptor pathway crosstalk on opioid analgesia, immune function, and gastrointestinal motility. Opioids non-stereoselectively activate the TLR4 pathway, and together with the subsequent release of pro-inflammatory cytokines such as IL-1 by glia, this TLR4 signaling initiates the central immune signaling response and modifies opioid pharmacodynamics. The DAMP HMGB1 is associated with the development of neuropathic pain. To explain morphine-induced persistent sensitization, a positive feedback loop has been proposed; this involves an initial morphine-induced amplified release of IL-1β and a subsequent exacerbated release of DAMPs, which increases the activation of TLR4 and the purinergic receptor P2X7R. Opioid receptor (μ, δ, and κ) agonists are involved in many aspects of immunosuppression. The intracellular TLR4/opioid receptor signaling pathway crosstalk induces the formation of the β-arrestin-2/TNF receptor-associated factor 6 (TRAF6) complex, which contributes to morphine-induced inhibition of LPS-induced TNF-α secretion in mast cells. A possible molecular mechanism is that the TLR4 pathway initially triggers the formation of the β-arrestin-2/TRAF6 complex, which is amplified by opioid receptor signaling, suggesting that β-arrestin-2 acts as a functional component of the TLR4 pathway.
10.3389/fimmu.2020.01455
Role of Innate Immune Receptor TLR4 and its endogenous ligands in epileptogenesis.
Paudel Yam Nath,Angelopoulou Efthalia,Akyuz Enes,Piperi Christina,Othman Iekhsan,Shaikh Mohd Farooq
Pharmacological research
Understanding the interplay between the innate immune system, neuroinflammation, and epilepsy might offer a novel perspective in the quest of exploring new treatment strategies. Due to the complex pathology underlying epileptogenesis, no disease-modifying treatment is currently available that might prevent epilepsy after a plausible epileptogenic insult despite the advances in pre-clinical and clinical research. Neuroinflammation underlies the etiopathogenesis of epilepsy and convulsive disorders with Toll-like receptor (TLR) signal transduction being highly involved. Among TLR family members, TLR4 is an innate immune system receptor and lipopolysaccharide (LPS) sensor that has been reported to contribute to epileptogenesis by regulating neuronal excitability. Herein, we discuss available evidence on the role of TLR4 and its endogenous ligands, the high mobility group box 1 (HMGB1) protein, the heat shock proteins (HSPs) and the myeloid related protein 8 (MRP8), in epileptogenesis and post-traumatic epilepsy (PTE). Moreover, we provide an account of the promising findings of TLR4 modulation/inhibition in experimental animal models with therapeutic impact on seizures.
10.1016/j.phrs.2020.105172
Spinal high-mobility group box-1 induces long-lasting mechanical hypersensitivity through the toll-like receptor 4 and upregulation of interleukin-1β in activated astrocytes.
Morioka Norimitsu,Miyauchi Kazuki,Miyashita Keita,Kochi Takahiro,Zhang Fang Fang,Nakamura Yoki,Liu Keyue,Wake Hidenori,Hisaoka-Nakashima Kazue,Nishibori Masahiro,Nakata Yoshihiro
Journal of neurochemistry
Intrathecal treatment with recombinant high-mobility group box-1 (rHMGB1) in naïve mice leads to a persistent and significantly decreased hind paw withdrawal threshold to mechanical stimuli, suggesting that spinal HMGB1 evokes abnormal pain processing. By contrast, repeated intrathecal treatment with anti-HMGB1 antibody significantly reverses hind paw mechano-hypersensitivity in mice with a partial sciatic nerve ligation (PSNL). By contrast, the cellular mechanism by which spinal HMGB1 induces neuropathic pain has yet to be fully elaborated. The current study tested the hypothesis that spinal HMGB1 could induce mechanical hypersensitivity through the activation of specific receptor in glial cells. Intrathecal pretreatment with toll-like receptor (TLR) 4 inhibitors, but not TLR5, receptor for advanced glycation end-products and C-X-C chemokine receptor type 4 inhibitors, prevented rHMGB1-evoked mechanical hypersensitivity. Activation of spinal astrocytes appears to be crucial for the mechanism of action of rHMGB1 in naïve mice, as intrathecal pretreatment with astrocytic inhibitors prevented the rHMGB1-induced mechanical hypersensitivity. Interleukin-1β (IL-1β) was up-regulated within activated astrocytes and block of TLR4 prevented the upregulation of IL-1β. Interleukin-1β appears to be secreted by activated astrocytes, as IL-1β neutralizing antibody prevented rHMGB1-induced mechanical hypersensitivity. Furthermore, intrathecal pretreatment with either MK801 or gabapentin prevented the rHMGB1-induced mechanical hypersensitivity, suggesting roles for spinal glutamate and the N-methyl-d-aspartate receptor in the mediation of rHMGB1-induced mechanical hypersensitivity. Thus, the current findings suggest that spinal HMGB1 upregulates IL-1β in spinal astrocytes through a TLR4-dependent pathway and increases glutamatergic nociceptive transduction. These spinal mechanisms could be key steps that maintain neuropathic pain.
10.1111/jnc.14812
Toll-like receptor 4 signaling: A common pathway for interactions between prooxidants and extracellular disulfide high mobility group box 1 (HMGB1) protein-coupled activation.
Zhang Yan,Karki Rajendra,Igwe Orisa J
Biochemical pharmacology
Necrotic cells passively release HMGB1, which can stimulate TLR4 in an autocrine fashion to potentially initiate "sterile" inflammation that maintains different disease states. We have shown that prooxidants can induce NF-κB activation through TLR4 stimulation. We examined whether prooxidants enhance HMGB1-induced TLR4 signaling through NF-κB activation. We used LPS-EK as a specific agonist for TLR4, and PPC and SIN-1 as in situ sources for ROS. As model systems, we used HEK-Blue cells (stably transfected with mouse TLR4), RAW-Blue™ cells (derived from murine RAW 264.7 macrophages) and primary murine macrophages from TLR4-KO mice. Both HEK-Blue and RAW-Blue 264.7 cells express optimized secreted embryonic alkaline phosphatase (SEAP) reporter under the control of a promoter inducible by NF-κB. We treated cells with HMGB1 alone and/or in conjunction with prooxidants and/or inhibitors using SEAP release as a measure of TLR4 stimulation. HMGB1 alone and/or in conjunction with prooxidants increased TNFα and IL-6 released from TLR4-WT, but not from TLR4-KO macrophages. Pro-oxidants increased HMGB1 release, which we quantified by ELISA. We used both fluorescence microscopy imaging and flow cytometry to quantify the expression of intracellular ROS. TLR4-neutralizing antibody decreased prooxidant-induced HMGB1 release. Prooxidants promoted HMGB1-induced NF-κB activation as determined by increased release of SEAP and TNF-α, and accumulation of iROS. HMGB1 (Box A), anti-HMGB1 and anti-TLR4-neutralizing pAbs inhibited HMGB1-induced NF-κB activation, but HMGB1 (Box A) and anti-HMGB1 pAb had no effect on prooxidant-induced SEAP release. The present results confirm that prooxidants enhance proinflammatory effects of HMGB1 by activating NF-κB through TLR4 signaling.
10.1016/j.bcp.2015.08.109
High-Mobility Group Box 1 Is Associated with the Inflammatory Pathogenesis of Graves' Orbitopathy.
Han So Young,Choi Soo Hyun,Shin Jeon-Soo,Lee Eun Jig,Han Sueng-Han,Yoon Jin Sook
Thyroid : official journal of the American Thyroid Association
High-mobility group box 1 (HMGB1) has been implicated in the pathogenesis of inflammatory autoimmune diseases. This study investigated the influence and mechanisms of HMGB1 in Graves' orbitopathy (GO). HMGB1 and its receptors (receptor for advanced glycation end products [RAGE], Toll-like receptor [TLR] 2, and TLR4) mRNA levels were evaluated by real-time polymerase chain reaction (RT-PCR) in GO and non-GO orbital tissues. The mRNA expressions of HMGB1 and its receptors were evaluated in primary cultured orbital fibroblasts from six GO patients and five healthy control subjects under interleukin (IL)-1β or tumor necrosis factor (TNF)-α stimulation using RT-PCR. HMGB1 secretions under IL-1β or TNF-α stimulation were evaluated by enzyme-linked immunosorbent assay (ELISA). The effects of an anti-HMGB1 antibody, RAGE antagonist (FPS-ZM1), and anti-TLR2 antibody on the expressions of IL-1β or TNF-α induced pro-inflammatory cytokines and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells were evaluated using ELISA and Western blot analysis, respectively. The plasma levels of HMGB1 were compared among patients with active GO ( = 51), inactive GO ( = 48), Graves' disease without GO ( = 30), and healthy control subjects ( = 46) by ELISA. The genes encoding HMGB1 and its receptors, as well as HMGB1 protein expression, were increased in GO orbital tissues compared to non-GO tissues. IL-1β and TNF-α stimulation increased the mRNA levels of HMGB1, RAGE, and TLR2 and the secretion of HMGB1 protein further in GO cells. Anti-HMGB1 antibody, FPS-ZM1, and anti-TLR2 antibody reduced IL-1β- or TNF-α-induced production of pro-inflammatory cytokines and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells. The plasma levels of HMGB1 were highly increased in patients with active GO, and were significantly correlated with the clinical activity score ( = 0.566, = 0.002) and levels of thyrotropin binding inhibitory immunoglobulin ( = 0.506, < 0.001). This study demonstrates an association of HMGB1 and its receptors in the inflammatory mechanisms of GO. HMGB1, RAGE, and TLR2 blockers reduced the production of pro-inflammatory molecules, providing a rationale for blocking the HMGB1 pathway to treat patients with GO. HMGB1 proteins were secreted further in the plasma of patients with active GO, suggesting that HMGB1 can be used as a biomarker of GO activity.
10.1089/thy.2018.0285
microRNA-30a inhibits the liver cell proliferation and promotes cell apoptosis through the JAK/STAT signaling pathway by targeting SOCS-1 in rats with sepsis.
Yuan Feng-Hua,Chen You-Lian,Zhao Ying,Liu Zhen-Mi,Nan Chuan-Chuan,Zheng Biao-Lin,Liu Xue-Yan,Chen Xiao-Yin
Journal of cellular physiology
Sepsis is a systemic inflammatory response that may be induced by trauma, infection, surgery, and burns. With the aim of discovering novel treatment targets for sepsis, this current study was conducted to investigate the effect and potential mechanism by which microRNA-30a (miR-30a) controls sepsis-induced liver cell proliferation and apoptosis. Rat models of sepsis were established by applying the cecal ligation and puncture (CLP) method to simulate sepsis models. The binding site between miR-30a and suppressor of cytokine signaling protein 1 (SOCS-1) was determined by dual luciferase reporter gene assay. The gain-of-and-loss-of-function experiments were applied to analyze the effects of miR-30a and SOCS-1 on liver cell proliferation and apoptosis of the established sepsis rat models. The expression of miR-30a, SOCS-1, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), Bcl-2 associated X protein (Bax), B cell lymphoma-2 (Bcl-2), toll-like receptor 4 (TLR4), and high-mobility group box 1 (HMGB1), and the extent of JAK2 and STAT3 phosphorylation were all determined. Sepsis led to an elevation of miR-30a and also a decline of SOCS-1 in the liver cells. SOCS-1 was negatively regulated by miR-30a. Upregulated miR-30a and downregulated SOCS-1 increased the expression of JAK2, STAT3, Bax, TLR4, and HMGB1 as well as the extent of JAK2 and STAT3 phosphorylation whereas impeding the expression of SOCS-1 and Bcl-2. More important, either miR-30a elevation or SOCS-1 silencing suppressed liver cell proliferation and also promoted apoptosis. On the contrary, the inhibition of miR-30a exhibited the opposite effects. Altogether, we come to the conclusion that miR-30a inhibited the liver cell proliferation and promoted cell apoptosis by targeting and negatively regulating SOCS-1 via the JAK/STAT signaling pathway in rats with sepsis.
10.1002/jcp.28410
Hypoxia enhances IL-10-producing B cell generation through upregulating high-mobility group B1 on tumor cell-released autophagosomes.
Zhang Yue,Pan Ning,Sheng Yemeng,Zhou Meng,Wen Zhifa,Chen Yongqiang,Huang Fang,Wang Li-Xin
Immunology letters
As common features of human solid tumors, hypoxia and nutrient starvation play multifaceted roles in cancer progress. However, the mechanisms are far from clear. Our previous work has indicated that tumor cell-released autophagosomes (TRAPs) are sufficient to suppress anti-tumor immune response in mouse by inducing IL-10-producing B cells through high-mobility group B1 (HMGB1). Here, we hypothesized that hypoxia or starvation might exert immunosuppressive effect through upregulating HMGB1 on TRAPs. We found that HMGB1 on TRAPs from human hepatocellular carcinoma cell line HepG2 played a significant role in IL-10-producing B cell induction. HMGB1 in tumor cells was upregulated under hypoxia and starvation, but only hypoxia significantly enhanced the level of HMGB1 present on the surfaces of TRAPs. Moreover, hypoxic TRAPs induced more IL-10-producing B cells with suppressive activities on CD4 and CD8 T cells. The finding indicates the role of TRAPs as a messenger of hypoxic response to enhance immunosuppression in tumor microenvironment.
10.1016/j.imlet.2019.09.005
HMGB1-TLR4 Axis Plays a Regulatory Role in the Pathogenesis of Mesial Temporal Lobe Epilepsy in Immature Rat Model and Children via the p38MAPK Signaling Pathway.
Yang Weihong,Li Jing,Shang Yun,Zhao Li,Wang Mingying,Shi Jipeng,Li Shujun
Neurochemical research
The HMGB1-TLR4 axis is activated in adult mouse models of acute and chronic seizure. Nevertheless, whether HMGB1 was involved in the pathogenesis of mesial temporal lobe epilepsy (MTLE) remains unknown. In this study, we first measured the dynamic expression patterns of HMGB1 and TLR4 in the hippocampi of a rat model and in children with MTLE, as well as the levels of TNF-α and IL-1β. In addition, HMGB1 was added to mimic the process of inflammatory response in neurons. Neuronal somatic size and dendritic length were measured by immunohistochemistry and digital imaging. The results showed that the expression of HMGB1 and TLR4 as well as the levels of TNF-α and IL-1β were higher in the three stages of MTLE development in the rat model and in the children with MTLE. HMGB1 increased the levels of TNF-α and IL-1β, upregulated the protein level of p-p38MAPK and promoted the growth of cell somatic size and dendritic length in neurons. Pre-treatment with p38MAPK inhibitor SB203580 decreased the levels of TNF-α and IL-1β, while downregulation of TLR4 significantly reduced HMGB1-induced p38MAPK signaling pathway activation. These data demonstrated that the HMGB1-TLR4 axis may play an important role in the pathogenesis of MTLE via the p38MAPK signaling pathway.
10.1007/s11064-016-2153-0
Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways.
Xu Xiang,Piao Hu-Nan,Aosai Fumie,Zeng Xiao-Yu,Cheng Jia-Hui,Cui Yue-Xian,Li Jing,Ma Juan,Piao Hu-Ri,Jin Xuejun,Piao Lian-Xun
British journal of pharmacology
BACKGROUND AND PURPOSE:Arctigenin, a major bioactive component of Fructus arctii, has been reported to have antidepressant-like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high-mobility group box 1 (HMGB1)/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies. EXPERIMENTAL APPROACH:The effects of chronic unpredictable mild stress (CUMS) on wild-type (WT) and TLR4 mice were examined. Antidepressant-like effects of arctigenin were tested using the CUMS-induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1- or TNF-α-stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF-α and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co-immunoprecipitation assays. KEY RESULTS:The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4 mice, compared with WT mice. Arctigenin exhibited antidepressant-like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF-α and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. CONCLUSIONS AND IMPLICATIONS:Arctigenin has antidepressant-like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression.
10.1111/bph.15261
Fibroblast growth factor 10 alleviates particulate matter-induced lung injury by inhibiting the HMGB1-TLR4 pathway.
Liu Lingjing,Song Chenjian,Li Jingli,Wang Qiang,Zhu Mingyang,Hu Yiran,Chen Junjie,Chen Chaolei,Zhang Jin-San,Dong Nian,Chen Chengshui
Aging
Exposure to particulate matter (PM) is associated with increased incidence of respiratory diseases. The present study aimed to investigate the roles of fibroblast growth factor 10 (FGF10) in PM-induced lung injury. Mice were intratracheally instilled with FGF10 or phosphate-buffered saline at one hour before instillation of PM for two consecutive days. In addition, the anti-inflammatory impact of FGF10 and its effect on the high-mobility group box 1 (HMGB1)-toll-like receptor 4 (TLR4) pathway was investigated. It was found that PM exposure is associated with increased inflammatory cell infiltration into the lung and increased vascular protein leakage, while FGF10 pretreatment attenuated both of these effects. FGF10 also decreased the PM-induced expression of interleukin (IL)-6, IL-8, tumor necrosis factor-α and HMGB1 in murine bronchoalveolar lavage fluid and in the supernatants of human bronchial epithelial cells exposed to PM. FGF10 exerted anti-inflammatory and cytoprotective effects by inhibiting the HMGB1-TLR4 pathway. These results indicate that FGF10 may have therapeutic values for PM-induced lung injury.
10.18632/aging.102676
Decreased inflammatory cytokine production of antigen-specific CD4 T cells in NMDA receptor encephalitis.
Dao Le-Minh,Machule Marie-Luise,Bacher Petra,Hoffmann Julius,Ly Lam-Thanh,Wegner Florian,Scheffold Alexander,Prüss Harald
Journal of neurology
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is the most common autoimmune encephalitis with psychosis, amnesia, seizures and dyskinesias. The disease is mediated by pathogenic autoantibodies against the NR1 subunit that disrupt NMDAR function. Antibody infusion into mouse brains can recapitulate encephalitis symptoms, while active immunization resulted also in strong T cell infiltration into the hippocampus. However, whether T cells react against NMDAR and their specific contribution to disease development are poorly understood. Here we characterized the ex vivo frequency and phenotype of circulating CD4 T helper (T) cells reactive to NR1 protein using antigen-reactive T cell enrichment (ARTE) in 24 patients with NMDAR encephalitis, 13 patients with LGI1 encephalitis and 51 matched controls. Unexpectedly, patients with NMDAR encephalitis had lower frequencies of CD154-expressing NR1-reactive T cells than healthy controls and produced significantly less inflammatory cytokines. No difference was seen in T cells reactive to the synaptic target LGI1 (Leucine-rich glioma-inactivated 1), ubiquitous Candida antigens or neoantigens, suggesting that the findings are disease-specific and not related to therapeutic immunosuppression. Also, patients with LGI1 encephalitis showed unaltered numbers of LGI1 antigen-reactive T cells. The data reveal disease-specific functional alterations of circulating NMDAR-reactive T cells in patients with NMDAR encephalitis and challenge the idea that increased pro-inflammatory NMDAR-reactive T cells contribute to disease pathogenesis.
10.1007/s00415-020-10371-y