Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation
Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation
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DOI：
10.1038/s41419-019-2217-6
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发表时间：
2020-01-13
影响因子：
9
通讯作者：
Yang Li
中科院分区：
文献类型：
--
作者：
Fan Xiaoli;Men Ruoting;Yang Li
自身免疫性肝炎（AIH）是一种与先天性和适应性免疫系统的相互作用细胞群相关的坏死性炎症疾病。传统树突状细胞（cDCs）对AIH的贡献及其机制仍知之甚少。AIH患者外周血成熟cDCs的频率增加，并与疾病严重程度呈正相关。在实验性自身免疫性肝炎（EAH）中，观察到成熟cDC的肝脏积累，沿着外周增加。EAH小鼠骨髓来源的树突状细胞（BMDC）比对照小鼠表现出更多的促炎功能。在体外，ConA处理促进BMDCs的成熟，其特征在于更高的MHC-II表达，共刺激分子和细胞因子分泌。ConA还可诱导DC表达自噬相关蛋白和自噬体的形成。为了进一步研究ConA诱导的DC活化是否与自噬相关，我们利用3-MA和巴弗洛霉素A1阻断自噬通量，并评估ConA诱导的DC的成熟和功能。3-MA和巴弗洛霉素A1抑制ConA诱导的BMDCs与CD 4 + T细胞共培养时的成熟状态和促炎细胞因子分泌，抑制CD 4 + T细胞的增殖和分化。我们证明了cDCs通过过度成熟参与AIH的发病机制。异常的自噬流在AIH中cDCs的免疫原性成熟中起着至关重要的作用，通过抑制自噬流来诱导耐受性cDCs可以被开发为AIH的新的治疗方法。
Autoimmune hepatitis (AIH) is a necroinflammatory disease associated with interactive cell populations of the innate and adaptive immune systems. The contribution of conventional dendritic cells (cDCs) to AIH and the underlying mechanism remain poorly understood. The frequency of peripheral mature cDCs increased in AIH patients and was positively correlated with disease severity. In experimental autoimmune hepatitis (EAH), hepatic accumulation of mature cDCs was observed, along with an increase in the periphery. Sequentially, bone marrow-derived dendritic cells (BMDC) from EAH mice exhibit more proinflammatory function than those from control mice. In vitro, ConA treatment promotes the maturation of BMDCs, which are characterized by higher expression of MHC-II, costimulatory molecules and cytokine secretion. ConA also induced the expression of autophagy-related protein and the formation of autophagosomes in DCs. To further investigate whether ConA-induced DC activation is associated with autophagy, we utilized 3-MA and bafilomycin A1 to block autophagy flux and accessed the maturation and function of DCs induced by ConA. 3-MA and bafilomycin A1 inhibited the mature status and proinflammatory cytokine secretion and diminished the proliferation and differentiation of CD4+ T cells when ConA-induced BMDCs cocultured CD4+ T cells. We demonstrated that cDCs contribute to the pathogenesis of AIH through excessive maturation. Aberrant autophagy flux plays a vital role in the immunogenic maturation of cDCs in AIH, and tolerogenic cDCs by inhibition of autophagy flux can be exploited as a new therapeutic approach for AIH.