IL-1R antagonist–deficient (Il1rn^−/−) mice develop autoimmune arthritis in which IL-17A plays a crucial role. Although many studies have shown that Th17 cell differentiation is dependent on TGF-β and IL-6, we found that Th17 cells developed normally in Il1rn^−/−Il6^−/− mice in vivo. Then, we analyzed the mechanisms of Th17 cell differentiation in Il1rn^−/−Il6^−/− mice. We found that IL-21 production was increased in the lymph nodes of Il1rn^−/− mice, naive Il6^−/− CD4⁺ T cells differentiated into Th17 cells when cultured with TGF-β and IL-21, and the differentiation was greatly enhanced when IL-1 was added to the culture. Th17 cell differentiation was not induced by either TGF-β or IL-1 alone or in combination. IL-21 induced IL-1R expression in naive CD4⁺ T cells, and IL-1 inhibited TGF-β–induced Foxp3 expression, resulting in the promotion of Th17 cell differentiation. Furthermore, IL-1 augmented the expression of Th17 cell–specific transcription factors such as Nfkbiz and Batf. These results indicate that excess IL-1 signaling can overcome the requirement of IL-6 in the differentiation of Th17 cells by suppressing Foxp3 expression and inducing Th17 cell–specific transcription factors.

Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.

NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM-caspase-8-ASC complex formation, resulting in the activation of caspase-8 and IL-1β release in microglia. Noncanonical inflammasome-derived IL-1β produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1β via noncanonical caspase-8-dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.

Relapsing polychondritis (RP) is an inflammatory disease of unknown causes, characterized by recurrent inflammation in cartilaginous tissues of the whole body. Recently, researchers have reported that, in mouse experiments, altered gut microbe-dependent T cell differentiation occurred in gut associated lymphoid tissues. Here, we investigated whether gut microbe alteration existed, and if so, the alteration affected peripheral T cell differentiation in patients with RP. In an analysis of gut microbiota, we found increased annotated species numbers in RP patients compared with normal individuals. In the RP gut microbiota, we observed several predominant species, namely Veillonella parvula, Bacteroides eggerthii, Bacteroides fragilis, Ruminococcus bromii, and Eubacterium dolichum, all species of which were reported to associate with propionate production in human intestine. Propionate is a short-chain fatty acid and is suggested to associate with interleukin (IL)10-producing regulatory T (Treg) cell differentiation in gut associated lymphoid tissues. IL10 gene expressions were moderately higher in freshly isolated peripheral blood mononuclear cells (PBMC) of RP patients than those of normal individuals. Six hours after the initiation of the cell culture, regardless of the presence and absence of mitogen stimulation, IL10 gene expressions were significantly lower in RP patients than those in normal individuals. It is well known that PBMC of patients with autoimmune and inflammatory diseases show hyporesponsiveness to mitogen stimulation. We suggest that, in RP patients, continuous stimulation of intestinal T cells by excessive propionate leads to the spontaneous IL10 production and a subsequent refractory period of T cells in patients with RP. The hyporesponsiveness of Treg cells upon activation may associate with inflammatory cytokine production of PBMC and subsequently relate to chondritis in RP patients.

The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6^−/− mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6^−/− mice and C1qtnf6^−/− embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H₂O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease exhibited most commonly in joints. We found that the expression of C1qtnf3, which encodes C1q/TNF-related protein 3 (CTRP3), was highly increased in two mouse RA models with different etiology. To elucidate the pathogenic roles of CTRP3 in the development of arthritis, we generated C1qtnf3(-/-) mice and examined the development of collagen-induced arthritis in these mice. We found that the incidence and severity score was higher in C1qtnf3(-/-) mice compared with wild-type (WT) mice. Histopathology of the joints was also more severe in C1qtnf3(-/-) mice. The levels of antibodies against type II collagen and pro-inflammatory cytokine mRNAs in C1qtnf3(-/-) mice were higher than WT mice. These observations indicate that CTRP3 plays an important role in the development of autoimmune arthritis, suggesting CTRP3 as a possible medicine to treat RA.