Naomi Hoshina

BACKGROUND: cell differentiation remains unknown. METHODS: cells. FINDINGS: cells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis. INTERPRETATION: cells, which suppress autoantibody production in the systemic lymphoid tissue, eventually ameliorating RA. Our findings provide mechanistic insights into the link between the gut environment and RA risk. FUNDING: This work was supported by AMED-Crest (16gm1010004h0101, 17gm1010004h0102, 18gm1010004h0103, and 19gm1010004s0104 to KH), the Japan Society for the Promotion of Science (JP17KT0055, JP16H01369, and JP18H04680 to KH; JP17K15734 to DT), Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects (KH), Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (DT), the SECOM Science and Technology Foundation (KH), the Cell Science Research Foundation (KH), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (DT), the Suzuken Memorial Foundation (KH and DT), the Takeda Science Foundation (KH and DT), The Science Research Promotion Fund, and The Promotion and Mutual Aid Corporation for Private Schools of Japan (KH).

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

Abstract Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA is associated with the expansion of Prevotellaceae and the under representation of the Clostridiumcluster XIVa, including Lachnospiraceae, which are major butyrate producers in the gut, although the pathological relevance has remained obscure. Here, we report that microbiota fermentation product butyrate controls the development of autoimmune arthritis in the host. We found that systemic autoantigen immunization causes hyperplasia of gut-associated lymphoid tissues by amplifying the germinal center (GC) reaction. Butyrate mitigated these pathological events by increasing Bcl-6+CXCR5+CD25−Foxp3+ follicular regulatory T (TFR) cells. Butyrate directly induced the differentiation of functional TFR cells by enhancing histone acetylation in TFR cell marker genes. The adoptive transfer of butyrate-induced TFR cells prevented autoimmune arthritis in mice. Notably, TFR cells induced by butyrate suppressed the development of autoreactive follicular helper T (TFH) and GCB cells and their migration from GALT into articulation-draining lymph nodes (DLNs). Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells which suppress the GC reaction and autoantibody production in the systemic lymphoid tissue, eventually ameliorating autoimmune arthritis. Our findings provide mechanistic insights into the link between the gut microbiota and RA risk.