1. Academic Validation
  2. Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation

Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation

  • Cell Death Dis. 2020 Jan 13;11(1):23. doi: 10.1038/s41419-019-2217-6.
Xiaoli Fan 1 Ruoting Men 1 Chen Huang 1 Mengyi Shen 1 Tingting Wang 1 Yasmeen Ghnewa 2 Yun Ma 2 Tinghong Ye 3 Li Yang 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, Chengdu, China.
  • 2 Institute of Liver Studies, King's College London Faculty of Life Sciences and Medicine at King's College Hospital, London, UK.
  • 3 Laboratory of Liver Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China. yeth1309@scu.edu.cn.
  • 4 Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, West China Hospital, Sichuan University, Chengdu, China. yangli_hx@scu.edu.cn.
Abstract

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.

Figures
Products