M2-polarized tumour-associated macrophages in stroma correlate with poor prognosis and Epstein-Barr viral infection in nasopharyngeal carcinoma.
Huang Haoran,Liu Xiong,Zhao Feipeng,Lu Juan,Zhang Bao,Peng Xiaohong,Zhang Mengwen,Chen Xiaomei,Li Gang,Li Xiangping
Acta oto-laryngologica
OBJECTIVES:To assess the relationships between CD163 expression, localization of CD163 macrophages, clinicopathological features and prognosis of NPC. METHODS:A total of 110 cases of NPC specimens and 80 cases of nasopharyngitis specimens were analysed for CD163 expression by immunohistochemistry and EBERs expression in situ hybridization. RESULTS:CD163 + macrophages in the tumour stroma were positively correlated with the tumour and nodal stage. Higher expression of Epstein-Barr virus-encoded RNAs (EBERs) in the nuclei of tumour cells was associated with higher density of CD163 + macrophages in the tumour stroma. More importantly, greater infiltration of CD163 + macrophages in the tumour stroma was associated with poor overall survival (OS) and poor progression-free survival (PFS). Multivariate analysis revealed that the density of CD163 macrophages in the tumour stroma may be an independent risk factor for NPC prognosis. CONCLUSIONS:Increased infiltration of CD163 macrophages in the tumour stroma correlates with worse outcomes and with Epstein-Barr virus (EBV) infection status of tumour cells in nasopharyngeal carcinoma (NPC).
10.1080/00016489.2017.1296585
The Role of Macrophage Migration Inhibitory Factor (MIF) in Asthmatic Airway Remodeling.
Li Ruyi,Wang Feiyun,Wei Jianghong,Lin Yun,Tang Guofang,Rao Lizong,Ma Libing,Xu Qing,Wu Jingjie,Lv Qian,Zhou Rui,Lei Huiren,Zhao Xueqiang,Yao Dong,Xiao Bo,Huang Haiming,Zhang Jiange,Mo Biwen
Allergy, asthma & immunology research
PURPOSE:Recent studies have demonstrated that macrophage migration inhibitory factor (MIF) is of importance in asthmatic inflammation. The role of MIF in modulating airway remodeling has not yet been thoroughly elucidated to date. In the present study, we hypothesized that MIF promoted airway remodeling by intensifying airway smooth muscle cell (ASMC) autophagy and explored the specific mechanisms. METHODS:MIF knockdown in the lung tissues of C57BL/6 mice was conducted by instilling intratracheally adeno-associated virus (AAV) vectors (MIF-mutant AAV9) into mouse lung tissues. Mice genetically deficient in the autophagy marker ATG5 (ATG5) was used to detect the role of autophagy in ovalbumin (OVA)-asthmatic murine models. Moreover, to block the expression of MIF and CD74 models, inhibitors, antibodies and lentivirus transfection techniques were employed. RESULTS:First, MIF knockdown in the lung tissues of mice showed markedly reduced airway remodeling in OVA murine mice models. Secondly, ASMC autophagy was increased in the OVA-challenged models. Mice genetically deficient in the autophagy marker ATG5 (ATG5) that were primed and challenged with OVA showed lower airway remodeling than genetically wild-type asthmatic mice. Thirdly, MIF can induce ASMC autophagy . Moreover, the cellular source of MIF which promoted ASMC autophagy was macrophages. Finally, MIF promoted ASMC autophagy in a CD74-dependent manner. CONCLUSIONS:MIF can increase asthmatic airway remodeling by enhancing ASMC autophagy. Macrophage-derived MIF can promote ASMC autophagy by targeting CD74.
10.4168/aair.2021.13.1.88
[Detection of peripheral blood Th1/Th2 and Tc1/Tc2 subsets in patients with condyloma acuminatum and its significance].
Zhu Ning,Cheng Hao,Zhu Ke-Jian,Zhang Xing,Xu Yan,Jiang Dong-Hai
Zhonghua shi yan he lin chuang bing du xue za zhi = Zhonghua shiyan he linchuang bingduxue zazhi = Chinese journal of experimental and clinical virology
OBJECTIVE:To investigate the role of T-helper (Th) and cytotoxic T (Tc) lymphocyte polarization in the pathogenesis of condyloma acuminatum (CA) and its correlation with recurrence. METHODS:Three-colour immunofluorescent flow cytometry was used to detect the proportion of CD3+ CD8- /IFN-gamma+ (Th1), CD3+ CD8- /IL-4+ (Th2), CD3+ CD8+/IFN-gamma+ (Tc1) and CD3+ CD8+ /IL-4+ (Tc2) cells in the peripheral blood of CA patients and health controls. RESULTS:Compared to health controls, CA patients showed a decreased number of Th1 (P < 0.01) and Tc1 cells (P < 0.05), as well as a decreased Th1/Th2 and Tc1/Tc2 ratio (P < 0.05). Furthermore, in 15 recurrent CA patients the ratio of Th1/Th2 was remarkably decreased (P < 0.01), while the ratio of Tc1/Tc2 had no significant change in comparison with health controls. CONCLUSION:The decrease of Th1 and Tc1 subsets results in relative Th2 and Tc2 predominance, and this tendency is more significant in recurrent CA patients. The Th1 to Th2 and Tc1 to Tc2 shifts in CA patients could be responsible for the fact that human papilloma virus (HPV) is hard to be eliminated.
Clinical Significance of M1/M2 Macrophages and Related Cytokines in Patients with Spinal Tuberculosis.
Disease markers
BACKGROUND:Macrophages are important immune cells involved in () infection. To further investigate the degree of disease development in patients with spinal tuberculosis (TB), we conducted research on macrophage polarization. METHODS:Thirty-six patients with spinal TB and twenty-five healthy controls were enrolled in this study. The specific morphology of tuberculous granuloma in spinal tissue was observed by hematoxylin-eosin (H&E) staining. The presence and distribution of bacilli were observed by Ziehl-Neelsen (ZN) staining. Macrophage-specific molecule CD68 was detected by immunohistochemistry (IHC). M1 macrophages play a proinflammatory role, including the specific molecule nitric oxide synthase (iNOS) and the related cytokine tumor necrosis factor- (TNF-) and interferon- (IFN-). M2 macrophages exert anti-inflammatory effects, including the specific molecule CD163 and related cytokine interleukin-10 (IL-10). The above markers were all detected by quantitative real-time PCR (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and IHC. RESULTS:Typical tuberculous granuloma was observed in the HE staining of patients with spinal TB. ZN staining showed positive expression of Ag85B around the caseous necrosis tissue and Langerhans multinucleated giant cells. At the same time, IHC results indicated that CD68, iNOS, CD163, IL-10, TNF-, and IFN- were expressed around the tuberculous granuloma, and their levels were obviously higher in close tissue than in the distant tissue. RT-PCR and ELISA results indicated that IL-10, TNF-, and IFN- levels of TB patients were also higher than those of the healthy controls. CONCLUSION:The report here highlights that two types of macrophage polarization (M1 and M2) are present in the tissues and peripheral blood of patients with spinal TB. Macrophages also play proinflammatory and anti-inflammatory roles. Macrophage polarization is involved in spinal TB infection.
10.1155/2020/2509454
M1 and M2 Macrophages: Oracles of Health and Disease.
Mills Charles D
Critical reviews in immunology
The purpose of immunology is simple. Cure or prevent disease. M1/M2 is useful because it is simple. M1/M2 describes the two major and opposing activities of macrophages. M1 activity inhibits cell proliferation and causes tissue damage while M2 activity promotes cell proliferation and tissue repair. Remarkably, the molecules primarily responsible for these "Fight" (NO) or "Fix" (Ornithine) activities both arise from arginine, and via enzymatic pathways (iNOS and arginase) that down regulate each other. The names M1 and M2 were chosen because M1 and M2 macrophages promote Th1 and Th2 responses, respectively. Products of Th1 and Th2 responses (e.g., IFN-γ, IL-4) also down regulate M2 and M1activity, respectively. Thus, M1/M2 demonstrated the importance of Innate Immunity and how it is linked to Adaptive Immunity in a beautifully counterbalanced system. "Civilization" and increased longevity present new disease challenges such as cancer and atherosclerosis that do not display classical "foreign" antigens. And, these diseases are often associated with (or caused by) M1- or M2- type responses that were formerly useful for fighting infections, but now are inappropriate in our increasingly "germ-free" societies. In turn, there is considerable potential for modulating M1 or M2 Innate responses in modern diseases to achieve better health. Finally, since M1 and Th1 (or M2 and Th2) often work in concert to produce characteristic immune responses and disease pathologies, it is recommended that Immune Type 1 or 2 (IT1, IT2) would be a simpler and unifying terminology going forward.
10.1615/critrevimmunol.v32.i6.10
Macrophages with regulatory functions, a possible new therapeutic perspective in autoimmune diseases.
Di Benedetto Paola,Ruscitti Piero,Vadasz Zahava,Toubi Elias,Giacomelli Roberto
Autoimmunity reviews
Macrophages are pivotal cells involved in chronic inflammatory and autoimmune diseases. In fact, during these diseases, activated macrophages may play a critical role, promoting the inflammation as well as mediating the damage resolution. This dichotomy is referred to two end-stage phenotypes of macrophages, conventionally known as M1 and M2, playing a pro-inflammatory and anti-inflammatory role, respectively. The M1 macrophages are the mainly subset involved during inflammatory processes, producing pro-inflammatory mediators. Conversely, the M2 macrophages are proposed to contribute to the resolution phase of inflammation, when cells with pro-resolving property are recruited and activated. In fact, this subset of macrophages may activate regulatory T lymphocytes, which play a critical role in the maintenance of peripheral tolerance and preventing the occurrence of autoimmune diseases. On these bases, the polarization toward the M2 phenotype could play a therapeutic role for autoimmune diseases. In this Review we discussed the characteristic of M1 and M2 macrophages, focusing on the immunoregulatory role of M2 cells and their potential ability to control the inflammation and to promote the immunological tolerance.
10.1016/j.autrev.2019.102369
Clinical experience with autologous M2 macrophages in children with severe cerebral palsy.
Chernykh Elena R,Kafanova Marina Yu,Shevela Ekaterina Ya,Sirota Sergei I,Adonina Elena I,Sakhno Lyudmila V,Ostanin Alexander A,Kozlov Vladimir V
Cell transplantation
Stem cell-based therapy is considered to be a new approach for the treatment of cerebral palsy (CP). Given the potent anti-inflammatory activity and high regenerative potential of M2 macrophages, these cells may be an alternative source for cell transplantation. To evaluate the safety and efficacy of autologous M2 macrophages, we conducted a pilot clinical trial in 21 children with severe CP. The primary outcome measure was safety, which included assessment of mortality of any cause, immediate adverse reactions, and serious adverse effects and comorbidities during 5-year follow-up. The secondary outcome measure was functional improvement in Gross Motor Function Measure (66-item GMFM) test, Peabody Developmental Motor Scale-Fine Motor (PDMS-FM) test, Ashworth scale, MRC scale, and an easy-to-understand questionnaire for evaluation of cognitive functions in our modification. Intradural injection of M2 cells (in mean dose of 0.8 × 10(6)/kg) into the lumbar spinal area did not induce any serious adverse events. No cases of mortality, psychomotor worsening, exacerbation of seizures, and long-term comorbidities, including tumors, were observed during a 5-year follow-up. After 3 months, GMFM score increased from 13.7 ± 7.8 to 58.6 ± 14.6, PDMS-FM score improved from 0.76 ± 0.42 to 5.05 ± 0.97, and the Ashworth score decreased from 3.8 ± 0.21 to 3.3 ± 0.24. Along with gross and fine motor function enhancement, an improvement of cognitive activity (from 1.62 ± 0.41 to 4.05 ± 0.64, according to questionnaire assessment) and reduction of seizure syndrome were registered as well. The neurological improvements did not diminish during the 5-year follow-up period. The data obtained suggest that cell therapy based on M2 macrophages is safe, does not induce early adverse effects and long-term comorbidities, and is accompanied with a significant improvement of motor and cognitive activities in severe CP patients. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
10.3727/096368914X684925
[Expression and prognostic value of regulatory T cells and M2 macrophages in diffuse large B-cell lymphoma tissues].
Xu Yuan-lin,Wang Hua-qing,Qian Zheng-zi,Song Zheng,Zhou Shi-yong,Zhang Hui-lai,Qiu Li-hua,Wang Xian-huo,Wang Ping
Zhonghua zhong liu za zhi [Chinese journal of oncology]
OBJECTIVE:To explore the prognostic value of regulatory T cells (Tregs) and M2 macrophages in diffuse large B-cell lymphoma (DLBCL) tissues. METHODS:The expression of CD163 and Foxp3 was detected by immunohistochemistry in 92 cases of DLBCL, and it was statistically analyzed whether their expressions correlate with clinical data and prognosis in patients with DLBCL. RESULTS:The density of M2 macrophage and regulatory T cells in DLBCL tumor tissues was significantly higher than that in the adjacent tissues (P = 0.02, P = 0.04). The expression of M2 macrophages was significantly positively correlated with regulatory T cells expression (r = 2.012, P < 0.05). High density of M2 or Tregs had a relationship with extranodal involvement (P < 0.05). Cox regression analysis showed that the expressions of CD163 and Foxp3 were independent prognostic factors of DLBCL (P < 0.05). CONCLUSIONS:Combined detection of the expression of CD163 and Foxp3 proteins and then evaluation of the amount of M2 macrophages and Tregs can be used to more closely predict the prognosis for DLBCL patients.
M2 macrophage is the predominant phenotype in airways inflammatory lesions in patients with granulomatosis with polyangiitis.
de Souza Alexandre Wagner Silva,van Timmeren Mirjan,Sanders Jan-Stephan,Stegeman Coen,Heeringa Peter,Kallenberg Cees G M,Westra Johanna
Arthritis research & therapy
BACKGROUND:Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to evaluate the distribution of M1 and M2 macrophage phenotypes in biopsies from the airways of patients with active granulomatosis with polyangiitis (GPA) and to analyze their associations with T and B cells in those biopsies, and with nasal carriage of Staphylococcus aureus, disease parameters and therapy. METHODS:Consecutive GPA patients (n = 35) with active airway disease, who underwent respiratory tract biopsy were included. Immunohistochemical evaluation was performed to assess the distribution of macrophages and T and B cells using the markers CD68, CD3 and CD20, respectively. CD86 was used as the M1 marker and CD163 as the M2 marker while Tbet and GATA-3 were used as Th1 and Th2 markers, respectively. At the time of the biopsy patients were assessed for nasal carriage of Staphylococcus aureus and treatment. RESULTS:Percentages of macrophages and T cells were significantly higher than those of B cells in lesional tissue from the respiratory tract in GPA. M2 macrophages and Th2 cells were more frequent than M1 macrophages (p = 0.0007) and Th1 cells (p < 0.0001), respectively. Percentages of T cells were higher in nose biopsies than in biopsies from other sites (p = 0.021); macrophages and CD163 macrophages were more predominant in biopsy sites other than the nose (p = 0.039 and p = 0.012, respectively). Carriage of Staphylococcus aureus was associated with higher T cell scores (p = 0.014). The frequency of macrophages, especially M2 macrophages, was higher in GPA patients treated with immunosuppressive agents (p = 0.010); daily prednisolone dose was positively correlated with all macrophage markers. However, in multivariate analysis no independent associations were found between disease parameters and therapy with macrophage markers or T cells. CONCLUSION:In GPA, M2 is the predominant macrophage phenotype in the respiratory tract. Although some associations were observed between macrophages and T cells with therapy and nasal carriage of Staphylococcus aureus, they were not independently significant in multivariate analysis.
10.1186/s13075-017-1310-4
Enhanced activity of macrophage M1/M2 phenotypes in periodontitis.
Yang Jingmei,Zhu Yan,Duan Dingyu,Wang Panpan,Xin Yuejiao,Bai Lin,Liu Yiying,Xu Yi
Archives of oral biology
OBJECTIVE:Monocytes/macrophages play a key role in mobilizing host defense against microbial infection. The selectivity of gene expression can turn macrophages into M1- or M2-type and the plasticity and differentiation of both M1 and M2 macrophages may play important roles in the development of periodontal disease. Our research aimed to study the association between the ratio of M1/M2 macrophage and inflammatory cytokines IL-1β, MMP-9, and investigate the expressions of M1-and M2-type macrophages in gingivitis and chronic periodontitis. METHODS:Forty specimens were collected from gingivitis individuals (n=20) and chronic periodontitis (n=20). Probing depth (PD), clinical attachment level (CAL), plaque index (PI) and bleeding on probing (BOP) were recorded. The expressions of M1- and M2-type macrophages are detected with immunohistochemical method and the relative expressions of M1-, M2-type macrophage, IL-1β and MMP-9 were assayed using real-time polymerase chain reactions. RESULTS:The M1 and M2 peptide were mainly observed in the cytoplasm of gingival connective tissue. The ratio of M1/M2 was significant higher in chronic periodontitis group compared with that in gingivitis one. In addition, the relative expressions of IL-1β and MMP-9 also increased in periodontitis group and was correlated with the ratios of M1/M2. Meanwhile, PD was positively correlated with ratios of M1/M2. CONCLUSIONS:Periodontal inflammation associates with an enhancement of ratio of M1/M2 phenotypes of macrophages. M1/M2 ratio could provide useful information on the periodontal tissue health status.
10.1016/j.archoralbio.2017.03.006
Status of M1 and M2 type macrophages in keloid.
Li Xuechuan,Wang Yu,Yuan Bo,Yang Huizhong,Qiao Liang
International journal of clinical and experimental pathology
Macrophages, differentiation from monocytes infiltrated in the wound, have been suggested to be involved and to play an important role in the pathogenesis of wound healing. Nevertheless, no evidence has been established regarding M1 and M2 type macrophages in Keloid. To understand the status of M1 and M2 type macrophages in keloid, immunohistochemistry was performed on 30 cases of Keloid tissues and normal controls, with CD68, typical surface marker for M1 and CD163, well-accepted marker for M2 being immunostained. Meanwhile, the glucocorticoid receptor NR3C1 was also detected. As further confirmation, quantitative real-time PCR was utilized to verify the expression of CD68, CD163 and NR3C1 on mRNA level. It was consistently shown that infiltrated M2 macrophages pronouncedly outnumbered M1 macrophages in the dermis of keloids; and that NR3C1 expression was significantly up-regulated in keloids than that in normal controls. In addition, there was a marked correlation between CD163 and NR3C1 expression. Our results suggest that the number of infiltrated M2 macrophages in the dermis of keloids may be linked to the responsiveness to glucocorticoids in the pathogenesis of keloid.
Comparison of CD163+ CD206+ M2 macrophages in the lesional skin of bullous pemphigoid and pemphigus vulgaris: the possible pathogenesis of bullous pemphigoid.
Furudate Sadanori,Fujimura Taku,Kambayashi Yumi,Kakizaki Aya,Aiba Setsuya
Dermatology (Basel, Switzerland)
BACKGROUND:M2 macrophages play a critical role in the induction of T helper 2 (Th2) polarization. METHODS:To investigate the contribution of M2 macrophages to the pathogenesis of bullous pemphigoid (BP) and pemphigus vulgaris (PV), we employed immunohistochemical staining for CD163 and CD206, as well as pSTAT1, pSTAT6, interleukin (IL)-4, IL-13, CCL17, CCL18 and Foxp3 in the lesional skin of 10 cases of BP and PV. RESULTS:The numbers of CD163+ CD206+ M2 macrophages were higher in BP than in PV. Moreover, pSTAT6+ cells, CCL17+ cells, CCL18+ cells and Foxp3+ regulatory T cells were prominent only in the lesional skin of BP. To further investigate the function of M2 macrophages, we examined the mRNA expression and production of Th2-related chemokines from M2 macrophages in vitro, which showed a significant increase in the mRNA expression and production of CCL18 when stimulated by IL-4 or IL-13. CONCLUSION:Our study sheds light onto one of the possible immunological mechanisms of BP and PV.
10.1159/000365946
Phytochemicals as modulators of M1-M2 macrophages in inflammation.
Saqib Uzma,Sarkar Sutripta,Suk Kyoungho,Mohammad Owais,Baig Mirza S,Savai Rajkumar
Oncotarget
Macrophages are critical mediators of the innate immune response against foreign pathogens, including bacteria, physical stress, and injury. Therefore, these cells play a key role in the "inflammatory pathway" which in turn can lead to an array of diseases and disorders such as autoimmune neuropathies and myocarditis, inflammatory bowel disease, atherosclerosis, sepsis, arthritis, diabetes, and angiogenesis. Recently, more studies have focused on the macrophages inflammatory diseases since the discovery of the two subtypes of macrophages, which are differentiated on the basis of their phenotype and distinct gene expression pattern. Of these, M1 macrophages are pro-inflammatory and responsible for inflammatory signaling, while M2 are anti-inflammatory macrophages that participate in the resolution of the inflammatory process, M2 macrophages produce anti-inflammatory cytokines, thereby contributing to tissue healing. Many studies have shown the role of these two subtypes in the inflammatory pathway, and their emergence appears to decide the fate of inflammatory signaling and disease progression. As a next step in directing the pro-inflammatory response toward the anti-inflammatory type after an insult by a foreign pathogen (e. g., bacterial lipopolysaccharide), investigators have identified many natural compounds that have the potential to modulate M1 to M2 macrophages. In this review, we provide a focused discussion of advances in the identification of natural therapeutic molecules with anti-inflammatory properties that modulate the phenotype of macrophages from M1 to M2.
10.18632/oncotarget.24788
M2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis.
de Carli Marina Lara,Miyazawa Marta,Nonogaki Suely,Shirata Neuza Kasumi,Oliveira Denise Tostes,Pereira Alessandro Antônio Costa,Hanemann João Adolfo Costa
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
BACKGROUND:Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by Paracoccidioides brasiliensis (Pb) and associated with deficient cellular immune response, which is modulated by inflammatory cells, mainly macrophages, and cytokines. Recently, the comprehension of the macrophage polarization mediated by Th1 and Th2 cytokines has contributed to elucidate the immune response that takes part in some diseases. Thus, the aim of this study was to assess the presence of Th1- and Th2-immune response and also Pb counting in oral lesions of chronic PCM. METHODS:Forty-eight cases of chronic PCM oral lesions were included. All cases were classified as loose or dense granulomas. S100 protein, IL-1β, IL-6, TNF-α, CD163 and CD68 immunoexpressions, and Pb localization were evaluated. The fungi present in the tissue were quantified by anti-Pb antibody. RESULTS:Most patients were white men with mean age of 47 years old and showed higher incidence of multiple lesions. Loose granulomas were predominant and exhibited a great amount of M2 macrophages, which were visualized with anti-CD163 antibody. The expression for CD163 and CD68 was similar (P = 0.05), highlighting the predominance of M2 macrophages in PCM. IL-1β, IL-6, and TNF-α immunoexpression did not significantly change with CD163, CD68, and S100 protein. The number of fungi was significantly higher in cases with intense IL-1β immunoexpression (P = 0.003). CONCLUSIONS:M2-activated macrophages were the majority among inflammatory cells in chronic PCM, characterizing the action of a Th2-immune response. Nevertheless, Th1 cytokines were also found; mainly IL-1β, which was associated with fungi counting in oral lesions.
10.1111/jop.12333
Immunophenotypic quantification of M1 and M2 macrophage polarization in radicular cysts of primary and permanent teeth.
Bertasso A S,Léon J E,Silva R A B,Silva L A B,de Queiroz A M,Pucinelli C M,Romualdo P C,Nelson-Filho P
International endodontic journal
AIM:To quantify M1 and M2 macrophages in radicular cysts of permanent (n = 14 cases) and primary teeth (n = 15 cases). METHODOLOGY:All patients who attended the School of Dentistry Ribeirão Preto, University of São Paulo with primary teeth or permanent molars that were scheduled for extraction and fulfilled the inclusion criteria: absence of pain; presence/absence of fistulae; extensive coronal destruction due to caries lesions without possibility of restoration; pulp necrosis; radiographically visible apical periodontitis; and no previous treatment, were selected. The radicular cysts were removed and subsequently submitted to histopathologic analysis in order to classify the type of inflammatory infiltrate. In addition, CD68 (M1+, M2+) and CD163 (M1-, M2+) markers were quantified through an immunohistochemistry analysis. The data acquired were submitted to a Mann-Whitney test, with a 5% significance level. RESULTS:The patients had a mean age of 38.6 years and 5.9 years for cysts associated with permanent and primary teeth, respectively. In the histopathological analysis, no significant difference (P = 0.87) was found between radicular cysts in primary and permanent teeth regarding the intensity of the chronic inflammatory infiltrate. A significantly greater prevalence of M2 macrophages (P < 0.05) was observed in the lesions of both permanent and primary teeth, even though both M1 and M2 macrophages were detected. No significant difference (P > 0.05) was found for M1 and M2 macrophages associated with the cysts of primary and permanent teeth. CONCLUSION:M1 and M2 macrophages were present in radicular cysts associated with primary and permanent teeth, with a greater quantity of M2 cells. The immunophenotypic quantification of M1 and M2 macrophage polarization in radicular cysts associated with primary and permanent teeth were similar.
10.1111/iej.13257
Significance of M2 macrophages in glomerulonephritis with crescents.
Li Jun,Yu Ya-Fen,Liu Chang-Hua,Wang Cui-Mei
Pathology, research and practice
OBJECTIVES:CD163 and CD206, markers of M2 macrophages, possesses anti-inflammatory properties. This study aims to investigate the clinicopathologic significance of M2 macrophages in patients of glomerulonephritis with crescents. METHODS:Renal tissue samples from patients of glomerulonephritis with more than 30% cell or cell-fibrous crescents, including lupus nephritis (LN, n=14), anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV, n=14), IgA nephropathy(IgAN) (n=11), Henoch Schonlein purpura glomerulonephritis(HSPGN)(n=8)were included in this study. The expression of CD163, CD206 and CD68 in renal tissues was detected by immunohistochemistry or immunofluorescence. RESULTS:(1) CD163 was mainly expressed in cell or cell-fibrous crescents, proliferative glomerular lesions and acute tubulointerstitial injury. There were numerous CD163-positive cells in LN and AAV in comparison with IgAN and HSPGN. (2) CD206-positive cells were mainly observed in acute tubulointerstitial injury, and proliferative glomerular lesions, especially in LN. Patients with LN had numerous CD206-positive cells in glomerular than other groups. The number of CD163-positive cells and CD206-positive cells in acute tubulointerstitial lesions of LN and AAV were more than IgAN and HSPGN. (3) Both the number of CD163-positive cells and CD206-positive cells in acute tubulointerstitial lesions negatively correlated to estimated glomerular filtration rate. (4) In LN, activity index (AI) positively correlated with the number of CD206-positive cells and CD163-positive cells. Dual staining showed that CD163-positive cells and CD206-positive cells also expressed CD68. CONCLUSIONS:CD163-positive cells and CD206-positive cells, subpopulation of macrophages, which were involved in the pathogenesis of active crescentic glomerulonephritis, especially in LN and AAV.
10.1016/j.prp.2017.04.011
Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review.
Tardito Samuele,Martinelli Giulia,Soldano Stefano,Paolino Sabrina,Pacini Greta,Patane Massimo,Alessandri Elisa,Smith Vanessa,Cutolo Maurizio
Autoimmunity reviews
BACKGROUND AND AIM:Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease; the clinical manifestations are correlated with continuum multiarticular synovitis, cartilage and bone damage, and defeat of joint function, that causes disability. Involvement of internal organs is also frequent. Between the inflammatory cells involved in RA, macrophages play a key role. These cells can polarize in different phenotype and mediate the immune/inflammatory reaction as well as the reparatory phase when possible. The properties of these cells are mediate by the body's environmental factors. In this systematic review, all English-speaking articles concerning the role of M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages in RA were systematically reviewed and categorized according to their polarized-function in RA, especially in the synovial tissue. Analyses of the endogenous molecules and the drugs that could modulate M1 and M2 activity in RA were achieved. METHODS:A sensitive search was developed in Pubmed, Web of Science, Ovid Med-Line, Embase Database and Science Direct Database (la both from Elsevier) to identify articles to increase the highlighting on the role of macrophages M1 and M2 in RA using the following terms: ((M1 AND M2) AND Rheumatoid Arthritis). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Relevant data were extracted and analyzed using a standardized template designed for this review. RESULTS:In total 39 resulting articles were selected and categorized according to description of M1/M2's role in RA. Data from humans, mice and rats were subcategorized, thus in every section were highlighted the contribute, in peripheral blood and synovial tissue, of both polarized macrophages; section for endogenous molecules and drugs that favor the switch from M1 to M2 macrophages were carried out. The most evinced relevant results, were that in RA blood and in the synovial tissue, there isn't a clear distinction phase with M1 or M2 macrophages (by membrane marker analysis); rather there is M1 and M2 subset disequilibrium and by deeply analyses of mRNA gene and cytokine produced, it emerged that a non-coherent expression inner marker match with membrane molecules, and also the tissue section can define the marker expressed. CONCLUSION:This systematic review emphasizes that the rigid classical subdivision of M1 and M2 macrophages, as well as the different samples' results comparison, might be questionable. In addition, it is suggested, when taking samples from RA patients, to carefully consider their therapies in order to analyze the M1 and M2 macrophages behavior without drug influence. In line with the advances in M1 and M2 knowledge, and the progression in the single-cell methodologies by identification of individual cell molecular markers, therapeutic approaches seem possible to favor the anti-inflammatory macrophage response in RA (e.g. M2 polarization).
10.1016/j.autrev.2019.102397
M1 and M2 macrophages differentially regulate hematopoietic stem cell self-renewal and ex vivo expansion.
Luo Yi,Shao Lijian,Chang Jianhui,Feng Wei,Liu Y Lucy,Cottler-Fox Michele H,Emanuel Peter D,Hauer-Jensen Martin,Bernstein Irwin D,Liu Lingbo,Chen Xing,Zhou Jianfeng,Murray Peter J,Zhou Daohong
Blood advances
Uncovering the cellular and molecular mechanisms by which hematopoietic stem cell (HSC) self-renewal is regulated can lead to the development of new strategies for promoting ex vivo HSC expansion. Here, we report the discovery that alternative (M2)-polarized macrophages (M2-MΦs) promote, but classical (M1)-polarized macrophages (M1-MΦs) inhibit, the self-renewal and expansion of HSCs from mouse bone marrow (BM) in vitro. The opposite effects of M1-MΦs and M2-MΦs on mouse BM HSCs were attributed to their differential expression of nitric oxide synthase 2 (NOS2) and arginase 1 (Arg1), because genetic knockout of and or inhibition of these enzymes with a specific inhibitor abrogated the differential effects of M1-MΦs and M2-MΦs. The opposite effects of M1-MΦs and M2-MΦs on HSCs from human umbilical cord blood (hUCB) were also observed when hUCB CD34 cells were cocultured with M1-MΦs and M2-MΦs generated from hUCB CD34 cells. Importantly, coculture of hUCB CD34 cells with human M2-MΦs for 8 days resulted in 28.7- and 6.6-fold increases in the number of CD34 cells and long-term SCID mice-repopulating cells, respectively, compared with uncultured hUCB CD34 cells. Our findings could lead to the development of new strategies to promote ex vivo hUCB HSC expansion to improve the clinical utility and outcome of hUCB HSC transplantation and may provide new insights into the pathogenesis of hematological dysfunctions associated with infection and inflammation that can lead to differential macrophage polarization.
10.1182/bloodadvances.2018015685
M2 macrophages coexist with a Th1-driven profile in periapical cysts.
Ribeiro C M,de Carli M L,Nonogaki S,Nogueira D A,Pereira A A C,Sperandio F F,Hanemann J A C
International endodontic journal
AIM:To evaluate the participation of both Th1 and Th2 responses in periapical cysts by assessing the presence of M2 macrophages, as well as acute IL-1 β, TNF-α and IL-6 cytokines. METHODOLOGY:Twenty-four cases of periapical cysts were selected. Immuno-expressions of IL-1 β, IL-6, TNF-α and CD163 were analysed in the cystic capsules in both superficial and deeper regions. Data were analysed with paired Wilcoxon test and Spearman correlation coefficient (P ≤ 0.05). RESULTS:There was a higher expression of IL-1β, IL-6, TNF-α and M2 macrophages in the superficial region (P < 0.001) of cystic capsules. All acute cytokines had significant positive correlations amongst them regardless of the cystic capsule region. Regarding CD163, positive correlations occurred only with TNF-α (P = 0.007; r = 0.537) and IL-6 (P = 0.018; r = 0.478) in the superficial regions of the cystic capsule. CONCLUSIONS:M2 macrophages participated actively in the inflammatory response of periapical cysts and correlated with the expression of certain acute Th1-related cytokines. This illustrates the coexistence of an acute and chronic Th2-driven immune response in these lesions. Although M2 macrophages favour the healing process, their presence is not sufficient for periapical cyst regression, once an acute active response has occurred due to an infectious stimuli.
10.1111/iej.12849
Roles of alternatively activated M2 macrophages in allergic contact dermatitis.
Suzuki Kotaro,Meguro Kazuyuki,Nakagomi Daiki,Nakajima Hiroshi
Allergology international : official journal of the Japanese Society of Allergology
Alternatively activated macrophages (M2 macrophages) play key roles in the suppression of Th1 cell responses and the orchestration of tissue repair. However, recent studies have shown that M2 macrophages have potentials to produce high levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, suggesting that M2 macrophages may exacerbate inflammation in some settings. In this regard, we have recently shown that large numbers of M2 macrophages accumulate in the sites of hapten-induced contact hypersensitivity (CHS), an animal model of allergic contact dermatitis, and that M2 macrophages exacerbate hapten-induced CHS by producing matrix metalloproteinase 12 (MMP12). We have also shown that suppressor of cytokine signaling-3 (SOCS3), a member of SOCS family proteins that are cytokine-inducible negative regulators of the JAK/STAT signaling pathways, is highly and preferentially expressed in M2 macrophages in hapten-induced CHS and that SOCS3 expressed in M2 macrophages is involved in the attenuation of CHS by suppressing MMP12 production. These findings underscore the importance of M2 macrophage-derived MMP12 in the development of CHS, and suggest that inhibition of M2 macrophages or MMP12 could be a potential therapeutic strategy for the treatment of allergic contact dermatitis.
10.1016/j.alit.2017.02.015
M2 macrophages and their role in rheumatic diseases.
Bhattacharya Shruti,Aggarwal Amita
Rheumatology international
As a component of the innate immune system, macrophages play a crucial role in host defense against a variety of microbes. Conventionally, macrophages have been classified as M1 and M2 depending on their phenotype and role in immune regulation. M1 macrophages are generally pro-inflammatory, while M2 (also known as alternatively activated macrophages) are anti-inflammatory. M1 macrophages release pro-inflammatory cytokines, reactive nitrogen, and oxygen intermediates, and kill pathogens, whereas their M2 counterparts participate in the resolution of inflammation, remodeling of tissue, angiogenesis, and tissue repair. Macrophages are also crucial in the pathogenesis of immune-inflammatory disorders, such as, arthritis. In this review, we discuss the markers of human M2 macrophages, the role played by them in inflammation or progression of rheumatic diseases, their potential to act as biomarkers, and, finally, therapeutic strategies aiming at altering/enhancing the macrophage phenotype.
10.1007/s00296-018-4120-3
M2 macrophages are closely associated with accelerated clavicle fracture healing in patients with traumatic brain injury: a retrospective cohort study.
Zhang Ran,Liang Yi,Wei Shuxiang
Journal of orthopaedic surgery and research
BACKGROUND:Mounting evidence indicate patients with traumatic brain injury (TBI) have an accelerated fracture healing. The healing process of bone fractures is greatly dependent on infiltrated macrophages. The macrophages are categorized into M1 or M2 phenotypes with different functions. This study is aimed to address the potential role of subtypes of macrophages in the process of fracture healing in patients with TBI. METHODS:Twenty-five cases of clavicle fracture alone (CF group) and 22 cases of clavicle fracture concomitant with TBI (CFT group) were retrospectively analyzed in this study. Callus tissues were harvested during operations. The expressions of COX-2, CD206, and CD68 were measured with immunohistochemistry. RESULTS:The percentages of M2 macrophages in total macrophages increased after bone fracture in both groups, while the percentages of M1-type macrophages are decreased. Interestingly, the increased percentages of M2 macrophages are significantly higher in CFT group than in CF group. Compared to CF group, the fracture callus volume was much larger (21.9 vs 8.5 cm) and the fracture healing time was much shorter (82.2 vs 127.0 days) in CFT group. The percentage of M2 macrophages was negatively correlated with fracture healing time in patients (r = - 0.575, p < 0.01). CONCLUSIONS:The findings suggest that the percentages of M2 macrophages in callus tissues increased dramatically during the repairing stage in both CF and CFT group. Percentages of M2 macrophages are associated with accelerated fracture healing in patients with TBI. M2 macrophage polarization during the stage of bone regeneration may play a vital role in promoting bone fracture healing.
10.1186/s13018-018-0926-7
M2 macrophages and regulatory T cells in lethal prostate cancer.
Erlandsson Ann,Carlsson Jessica,Lundholm Marie,Fält Anna,Andersson Sven-Olof,Andrén Ove,Davidsson Sabina
The Prostate
BACKGROUND:Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (T ) can contribute to cancer progression by suppressing the anti-tumor immune response. This study investigated the number of CD163-positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and T . METHODS:This nested case-control study included subjects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infiltrating CD163-positive M2 macrophages and FOXP3/CD4-positive T in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and T were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts. RESULTS:The number of M2 macrophages and T showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis. CONCLUSIONS:Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as T , promote an immunosuppressive environment.
10.1002/pros.23742
High density of M2-macrophages in acral lentiginous melanoma compared to superficial spreading melanoma.
Zúñiga-Castillo Miguel,Pereira Naiura V,Sotto Mirian N
Histopathology
AIMS:Acral lentiginous melanoma (ALM) is the most common type of melanoma in people with darker skin phototypes. There is some evidence that the aetiology, pathogenesis, risk factors and natural history of ALM differ from those of superficial spreading melanoma (SSM). ALM behaves more aggressively than SSM, but the biological explanation for these differences remains unknown. The presence of one subtype of macrophages, termed M2-macrophage (M2-M), has been found to be related to local progression, metastasis and poor prognosis in several neoplasms. The aim of this study was to compare the density of M2-Ms in ALMs versus SSMs, and to examine whether or not the density of M2-Ms is associated with histopathological features predictive of adverse prognosis in cutaneous melanoma (CM), as well as development of metastasis. METHODS AND RESULTS:Sixty-seven ALMs and 67 SSMs cases were analysed. The tumours were classified according to thickness, ulceration, mitosis and metastasis. M2-M quantity was evaluated using immunohistochemistry with anti-CD163 and anti-CD206 antibodies. M2-Ms were increased in ALM compared with SSM, and were related to the histopathological features predictive of adverse prognosis in CM, such as thickness > 1.0 mm, ulceration and mitotic activity, and the development of metastasis. CONCLUSIONS:Our study is the first, to our knowledge, to demonstrate the increased presence of M2-Ms in ALM compared with SSM. Our findings suggest that the increased M2-Ms in ALM are associated with the main histopathological features predictive of adverse prognosis in CM, as well as the presence of metastasis, and that these cells can be related to the aggressive behaviour seen in ALMs.
10.1111/his.13478
The number and localization of CD68+ and CD163+ macrophages in different stages of cutaneous melanoma.
Melanoma research
The role of tumor-associated macrophages (TAMs) in cutaneous melanoma is controversial. TAMs include immunogenic and immunosuppressive subtypes, and have distinct functions according to their microanatomical localization. Our aim was to investigate TAMs in benign, premalignant, and malignant melanocytic lesions to determine possible associations with tumor progression and clinicopathological characteristics. In total, 184 tissue samples, including benign and dysplastic nevi, in-situ melanomas, superficial (Breslow's depth <1 mm), and deep (Breslow's depth >4 mm) invasive melanomas and lymph node metastases, were analyzed for macrophage content. Samples were stained immunohistochemically for CD68 and CD163, representing all TAMs and M2-macrophages, respectively. Macrophages were counted by hotspot analysis, and assessed semiquantitatively from the tumor cell nests and stromal component of malignant cases. CD68+ and CD163+ TAMs were more abundant in invasive melanomas compared with benign nevi. The proportion of TAMs in the tumor nests was higher in deep melanomas and lymph node metastases compared with superficially invasive melanomas. High amounts of CD68+ macrophages in tumor cell nests were associated with recurrence, whereas low CD163+ macrophage proportion in tumor stroma was associated with recurrence and in primary melanomas also with poor overall survival. TAMs seem to promote tumor progression in cutaneous melanoma. In particular, CD68+ TAMs and their abundance in tumor nests were associated with poor prognostic factors. However, the correlation of low stromal CD163+ TAM proportion with a poor prognosis indicates that the role of TAMs depends on their subtype and microanatomical localization.
10.1097/CMR.0000000000000522
Macrophages participate in the immunosuppression of condyloma acuminatum through the PD-1/PD-L1 signaling pathway.
Liao Li-Chao,Hu Bai,Zhang Si-Ping
Journal of the Chinese Medical Association : JCMA
BACKGROUND:The aim of this study was to investigate whether macrophages can participate in the immunosuppression of condyloma acuminatum (CA) by expressing PD-1/PD-L1. METHODS:The infiltration of macrophages and expression of programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1) on wart lesions and in normal skin tissues were detected by immunohistochemistry assay. The amounts of M1- and M2-type macrophages derived from THP-1 cells were measured by flow cytometry. The expression of cytokines on macrophages was examined by using enzyme-linked immunosorbent assay (ELISA). The protein expression of PD-1 and PD-L1 on macrophages was detected by western blotting. RESULTS:The macrophages were significantly increased, while PD-1 and PD-L1 were highly expressed on wart lesions compared to normal controls. More M2-like macrophages than M1-type macrophages were present on wart lesions. The M2-like macrophages in the CA groups showed high expression of interleukin-10 (IL-10), transforming growth factor (TGF-β), PD-1, and PD-L1 compared to normal controls. CONCLUSION:Macrophages participate in the immunosuppression of CA by expressing PD-1/PD-L1.
10.1097/JCMA.0000000000000090