Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells
Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells
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DOI：
10.1016/j.ebiom.2020.102913
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发表时间：
2020-07
期刊：
影响因子：
11.1
通讯作者：
D. Takahashi;Naomi Hoshina;Yuma Kabumoto;Y. Maeda;A. Suzuki;Hiyori Tanabe;Junya Isobe;Takahiro Yamada;Kisara Muroi;Yuto Yanagisawa;A. Nakamura;Yumiko Fujimura;Aiko Saeki;Mizuki Ueda;Ryohtaroh Matsumoto;Hanako Asaoka;J. Clarke;Yohsuke Harada;E. Umemoto;N. Komatsu;T. Okada;H. Takayanagi;K. Takeda;M. Tomura;K. Hase
中科院分区：
文献类型：
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作者：
D. Takahashi;Naomi Hoshina;Yuma Kabumoto;Y. Maeda;A. Suzuki;Hiyori Tanabe;Junya Isobe;Takahiro Yamada;Kisara Muroi;Yuto Yanagisawa;A. Nakamura;Yumiko Fujimura;Aiko Saeki;Mizuki Ueda;Ryohtaroh Matsumoto;Hanako Asaoka;J. Clarke;Yohsuke Harada;E. Umemoto;N. Komatsu;T. Okada;H. Takayanagi;K. Takeda;M. Tomura;K. Hase
类风湿性关节炎(RA)是一种慢性衰弱性自身免疫性疾病，发病率高，尤其在工业化国家。已观察到类风湿关节炎患者肠道微生物区系失调。例如，新发的未经治疗的类风湿性关节炎(NORA)与梭状芽胞杆菌簇XIVa的表达不足有关，包括乳杆菌属，这是丁酸的主要产生者，尽管病理相关性仍不清楚。滤泡调节性T(TFR)细胞在包括RA在内的自身免疫性疾病的发病机制中起着重要的调节作用。循环中TFR细胞数量的减少与RA自身抗体的升高和疾病的严重程度有关。然而，共生微生物来源的丁酸盐在控制TFR细胞分化中的作用尚不清楚。方法我们利用胶原性关节炎(CIA)和SKG关节炎模型研究了微生物来源的丁酸盐在控制自身免疫性关节炎中的作用。在CIA模型中，我们对结肠和关节引流淋巴结中的肠道相关淋巴组织(GALT)中的自身免疫反应进行了表型分析。我们建立了CXCR5+Bcl6+Foxp3+TFR(ITFR)细胞体外培养体系，并检测了丁酸盐是否促进了iTFR细胞的分化。II型胶原(CII)免疫可在CIA发病前放大GC反应，导致结肠GALT肥大。丁酸盐通过促进TFR细胞分化减轻这些病理事件。丁酸盐通过促进TFR细胞标志基因的组蛋白乙酰化，在体外直接诱导功能性TFR细胞分化。这种作用归因于丁酸对组蛋白脱乙酰酶(HDAC)的抑制，导致TFR细胞标记基因启动子区域的组蛋白超乙酰化。丁酸处理的iTFR细胞的过继转移减少了CII特异性自身抗体的产生，从而改善了关节炎的症状。相应地，微生物区系衍生的丁酸盐作为一种环境线索来增强TFR细胞，TFR细胞抑制系统淋巴组织中自身抗体的产生，最终改善RA。这项工作得到了Amed-Crest(16gm1010004h0101、17gm1010004h0102、18gm1010004h0103和19gm1010004s0104 to KH)、日本科学促进会(JP17KT0055、JP16H01369和JP18H04680 to KH；这些机构包括日本国立卫生研究院(JP17K15734至DT)、庆应义乌大学创新合作研究项目特别助学金(KH)、福泽庆雄教育研究促进纪念基金(DT)、SECOM科学技术基金会(KH)、细胞科学研究基金会(KH)、本田医学和药物研究纪念基金会(DT)、铃木纪念基金会(KH和DT)、武田科学基金会(KH和DT)、科学研究促进基金、以及日本私立学校促进互助公司(KH)。
BackgroundRheumatoid 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 (NORA) is associated with the underrepresentation of theClostridiumcluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure. Follicular regulatory T (TFR) cells play critical regulatory roles in the pathogenesis of autoimmune diseases, including RA. Reduced number of circulating TFRcells has been associated with the elevation of autoantibodies and disease severity in RA. However, the contribution of commensal microbe-derived butyrate in controlling TFRcell differentiation remains unknown.MethodsWe examined the contribution of microbe-derived butyrate in controlling autoimmune arthritis using collagen-induced arthritis (CIA) and SKG arthritis models. We phenotyped autoimmune responses in the gut-associated lymphoid tissues (GALT) in the colon and joint-draining lymph nodes in the CIA model. We developed anin vitroCXCR5+Bcl-6+Foxp3+TFR(iTFR) cell culture system and examined whether butyrate promotes the differentiation of iTFRcells.FindingsMicrobe-derived butyrate suppressed the development of autoimmune arthritis. The immunization of type II collagen (CII) caused hypertrophy of the GALT in the colon by amplifying the GC reaction prior to the onset of the CIA. Butyrate mitigated these pathological events by promoting TFRcell differentiation. Butyrate directly induced the differentiation of functional TFRcellsin vitroby enhancing histone acetylation in TFRcell marker genes. This effect was attributed to histone deacetylase (HDAC) inhibition by butyrate, leading to histone hyperacetylation in the promoter region of the TFR-cell marker genes. The adoptive transfer of the butyrate-treated iTFRcells reduced CII-specific autoantibody production and thus ameliorated the symptoms of arthritis.InterpretationAccordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFRcells, 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.FundingThis 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).