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The therapeutic effect of myeloid-derived suppressor cells (MDSCs) in mice with collagen-induced arthritis (CIA) remains controversial. We analyzed the role of exosomes derived from granulocytic MDSCs (G-MDSCs) in CIA and explored the potential mechanism underlying the immunosuppressive effect. In CIA mice, G-MDSC-derived exosomes (G-exo) efficiently reduced the mean arthritis index, leukocyte infiltration and joint destruction. G-exo decreased the percentages of Th1 and Th17 cells both in vivo and in vitro. The miR-29a-3p and miR-93-5p contained in G-exo were verified to inhibit Th1 and Th17 cell differentiation by targeting T-bet and STAT3, respectively. Notably, the delivery of exogenous miR-29a-3p and miR-93-5p enhanced the ability of bone marrow-derived G-exo to attenuate arthritis progression in CIA mice. Exosomes derived from human MDSCs, which overexpressed miR-29a-3p and miR-93-5p, suppressed Th1 and Th17 cell differentiation in vitro. These data showed that G-exo alleviated CIA by suppressing Th1 and Th17 cell responses. Mechanistically, miR-29a-3p and miR-93-5p were verified to inhibit the differentiation of Th1 and Th17 cells, respectively. Our findings demonstrated the therapeutic potential of G-MDSC-derived exosomal miRNAs in autoimmune arthritis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and subsequent joint destruction. Previous studies have confirmed that Th17 cells play a critical role in the pathogenesis of RA. MicroRNA (miR)-301a-3p is a regulatory factor for Th17 cells differentiation that contributes to the pathogenesis of autoimmune diseases. The purposes of this study were to identify the alteration of Th17 cells and analyze the correlation between the expression of the miR-301a-3p and the proportion of Th17 cells in RA patients. The results showed that the frequency of Th17 cells and the expression of transcription factors (RORγt and STAT3) significantly increased in the peripheral blood mononuclear cells (PBMCs) from RA patients, and the associated proinflammatory cytokines were also upregulated. We also observed that the expression of protein inhibitor of activated STAT3 (PIAS3), the main cellular inhibitor of STAT3, was attenuated in RA patients and negatively correlated with the percentage of Th17 cells in RA. Interestingly, miR-301a-3p, an inhibitor of PIAS3 expression, was overexpressed in the PBMCs from RA patients and positively correlated with the frequency of Th17 cells in patients with RA. Taken together, these data indicated that miR-301a-3p and Th17 cells were augmented in peripheral blood, which may play an important role in the process of RA.

The glucocorticoid-induced TNFR family-related protein (GITR) and its ligand play a critical role in the pathogenesis of autoimmune arthritis by enhancing the Th17 cell response, but their molecular mechanisms remain largely unclear. This study aims to define the role of p38 mitogen-activated protein kinases (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling in GITRL-induced Th17 cells in autoimmune arthritis. We found that the p38 phosphorylation was enhanced by GITRL in activated CD4+T cells, and the p38 inhibitor restrained the GITRL-induced Th17 cell expansion in a dose-dependent manner. Moreover, there was decreased STAT3 activity on Tyr705 and Ser727 with the p38 inhibitor in vitro. Notably, the p38 inhibitor could prevent GITRL-treated arthritis progression and markedly decrease the Th17 cell percentages. The phosphorylation of the Tyr705 site was significantly lower in the GITRL-treated CIA mice administrated with the p38 inhibitor. A significantly higher phosphorylation of p38 was detected in RA patients and had a positive relationship with the serum level of anti-cyclic citrullinated peptide (anti-CCP) antibody. Our findings have indicated that GITRL could promote Th17 cell differentiation by p38 MAPK and STAT3 signaling in autoimmune arthritis.

Objective: To investigate the immunostimulatory role of Propionibacterium acnes (P. acnes) in the differentiation of dendritic cell maturation and T helper (Th) subsets, and further explore the potential mechanism of its granuloma-inducing effect., Methods: After the mouse bone marrow-derived dendritic cells (BMDCs) were stimulated by P. acnes, the expressions of co-stimulatory molecules CD40, CD80, CD86 and major histocompatibility complex II (MHCII) on BMDCs were detected by flow cytometry, the mRNA levels of inflammatory cytokines IL-12, IL-6 and IL-23 were measured by real-time quantitative PCR (qRT-PCR), and the protein concentrations of corresponding cytokines were analyzed by ELISA. Thereafter, BMDCs were cultured in the presence of P. acnes and CD4(+) T cells, and the percentages of Th1 and Th17 cells were detected by flow cytometry. In addition, murine model of liver granuloma was constructed by injecting heat-killed P. acnes through tail vein, and the mRNA levels of IL-17 and IFN-γ were measured by qRT-PCR., Results: P. acnes up-regulated the expressions of CD40, CD80, CD86 and MHCII on BMDCs, and the mRNA and protein levels of the IL-12, IL-6 and IL-23 cytokines were also higher on P. acnes-treated BMDCs compared with non-stimulated BMDCs. Furthermore, the percentages of Th1 and Th17 cells in the co-culture system increased. In addition, the mRNA levels of IL-17 and IFN-γ were elevated obviously in the liver with abundant granulomas after P. acnes treatment., Conclusion: P. acnes could activate BMDCs, promote the differentiation of Th1 and Th17 cells, and further induce the formation of granulomas.

Hashimoto's thyroiditis (HT) is an organ-specific immune disease characterized by the presence of lymphocytic infiltration and serum autoantibodies. Previous studies have confirmed the critical role of Th17 cells in the pathopoiesis of HT patients. Additionally, regulatory T cells (Treg) display a dysregulatory function in autoimmune disease. The purpose of this study is to investigate the alteration of Th17 and Treg cells in HT patients and explore contributing factors. We found there was an increased ratio of Th17/Treg in HT patients and a positive correlation with autoantibodies (anti-TgAb). In addition, there was an increased level of GITRL, which has been demonstrated to be correlated with the increassement of Th17 cells in the serum and thyroid glands of HT patients; the upregulated serum level of GITRL has a positive correlation with the percentage of Th17 cells in HT patients. In summary, an increase in GITRL may impair the balance of Th17/Treg, and contribute to the pathopoiesis of Hashimoto's thyroiditis.

Background: Obesity has become a global challenge for public health. It has been reported that obesity is associated with chronic inflammation. However, the mechanism for the chronic inflammation contributes to obesity remains elusive., Methodology/principal Findings: In our study, we found a novel CD11c+ dendritic cell subset existed in murine adipose tissues which was immature phenotype. Moreover, as compared to the lean controls, the number of CD11c+ DCs and CD4+IL-17+T cells were higher in adipose tissue of high fat diet (HFD) mice. Adipose tissues derived dendritic cells (ATDCs) displayed lower levels of CD40, CD80, CD86, MHCI and MHCII expression than splenic DCs (SPDCs). However, ATDCs showed higher levels of IL-6, TGF-β and IL-23 secretion. Moreover, our in vitro experiments demonstrated that ATDCs were capable of promoting Th17 cell generation., Conclusions/significance: Our results indicate the existence of CD11c+ DCs in adipose tissues, which displays an immature phenotype but possessing pro-inflammatory function.

It was reported that IL-17 had been detected in the inflammatory infiltrates of patients with DM (dermatomyositis). In this study, we investigated the frequency of Th17 cells and the expression of microRNA-206 (miR-206) in DM patients. Firstly, we observed that the frequency of Th17 cells and the expression of transcription factors were increased significantly in the PBMCs of DM patients. Secondly, we found that there was a positive correlation between the percentages of Th17 cells and serum level of CK in DM patients. And the serum concentrations of IL-6, IL-1β, TGF-β, and IL-23, the important cytokines of Th17 differentiation, were increased in DM patients. It was predicted that Krüppel-like factor 4 (KLF4) is one of the multiple targets of miR-206. We detected the expression of miR-206 in DM patients, and it was decreased in the serum and PBMCs of DM patients. The augmented expression of KLF is accompanied by the attenuated expression of miR-206. Furthermore, a negative correlation between the percentages of Th17 cells and the expression of miR-206 in DM patients has been found. Taken together, these findings suggest the attenuated expression of miR-206, and the augmented frequency of Th17 cells in DM patients.

Circular RNAs (circRNAs) are important transcriptional regulators of genome expression that participate in the pathogenesis of human diseases. Mechanistically, circRNAs, as competitive endogenous RNAs (ceRNAs), can sponge microRNAs (miRNAs) with miRNA response elements. A previous study identified that hsa_circ_0089172 (circNUP214) is abnormally expressed in Hashimoto's thyroiditis. However, the role of circNUP214 in rheumatoid arthritis (RA) remains unclear. In total, 28 RA patients and 28 healthy controls were enrolled in this study. We found that circNUP214 is an abundant and stable circRNA in RA patients that can potentially differentiate RA patients from healthy subjects. Additionally, the elevated levels of IL-23R positively correlated with circNUP214 expression. The knockdown of circNUP214 resulted in the reduction of IL-23R at both transcriptional and translational levels in human CD4+ T cells. The proportion of circulating Th17 cells and the transcript levels of IL-17A were increased in RA patients and were both positively correlated with IL-23R expression. Moreover, positive correlations between the transcript levels of circNUP214 and the percentage of Th17 cells and the transcript levels of IL-17A were observed in RA patients. The downregulation of circNUP214 decreased the proportion of Th17 cells and the transcript levels of IL-17A in vitro. Furthermore, circNUP214 functioned as a ceRNA for miR-125a-3p in RA patients. Taken together, our results indicate that elevated levels of circNUP214 contribute to the Th17 cell response in RA patients. [ABSTRACT FROM AUTHOR]

It is widely acknowledged that a close relationship is between inflammation and colon cancer. Interleukin (IL)-17A and myeloid-derived suppressor cells (MDSCs) play an important role in the development of colitis-associated cancer (CAC). However, the precise changes of IL-17, MDSCs, and Th17 cells during the CAC progression have not been observed in the colorectal chronic inflammation-dependent tumor. In this study, we found the level of IL-17 was increased in pathogenic colon site during the early stage of CAC model. Further experiments showed the increased IL-17 was probably secreted by peritoneal macrophages when exposed to dextran sulfate sodium (DSS). In vitro, we found that IL-17 could enhance survival and suppressive function of granulocytic (G)-MDSCs, the subset associated with inflammation. With the development of CAC, the proportions of MDSCs and Th17 cells were continuously increased by the high level of IL-17 produced by macrophages. However, the increase of MDSCs was earlier and acuter than that of Th17 cells. Selective depletion of MDSCs not only slowed down CAC process but also significantly reduce Th17 cells in vivo. Thereafter, we demonstrated that in the development of CAC, IL-17 secreted by peritoneal macrophages could promote the accumulation of G-MDSCs, then the proportion of Th17 cells was increased, and finally promote the development of CAC. [ABSTRACT FROM AUTHOR]