Wang J, Cao X, Zhao J, Zhao H, Wei J, Li Q, Qi X, Yang Z, Wang L, Zhang H, Bai L, Wu Z, Zhao L, Hong Z, Yin Z
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
The First Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, China.
Clin Exp Immunol. 2017 Apr;188(1):127-137. doi: 10.1111/cei.12907. Epub 2017 Jan 5.
Dendritic cells (DCs) play critical roles in initiating and regulating innate immunity as well as adaptive immune responses. However, the role of conventional dendritic cells (cDCs) in concanavalin A (ConA)-induced fulminant hepatitis is unknown. In this study, we demonstrated that depletion of cDCs using either CD11c-diphtheria toxin receptor transgenic mice (DTR Tg) mice or anti-CD11c antibody reduced the severity of liver injury significantly, indicating a detrimental role of cDCs in ConA-induced hepatitis. We elucidated further the pathological role of cDCs as being the critical source of interleukin (IL)-12, which induced the secretion of interferon (IFN)-γ by natural killer (NK) T cells. Reconstitution of cDCs-depleted mice with IL-12 restored ConA-induced hepatitis significantly. Furthermore, we determined that NK T cells were the target of DC-derived IL-12, and NK T cells contributed to liver inflammation and injury through production of IFN-γ. In summary, our study demonstrated a novel function of cDCs in mediating ConA-induced hepatitis through regulating IFN-γ secretion of NK T cells in an IL-12-dependent fashion. Targeting cDCs might provide potentially therapeutic applications in treating autoimmune related liver diseases.
树突状细胞（DCs）在启动和调节固有免疫以及适应性免疫反应中发挥着关键作用。然而，传统树突状细胞（cDCs）在伴刀豆球蛋白A（ConA）诱导的暴发性肝炎中的作用尚不清楚。在本研究中，我们证明，使用CD11c-白喉毒素受体转基因小鼠（DTR Tg）或抗CD11c抗体清除cDCs可显著降低肝损伤的严重程度，表明cDCs在ConA诱导的肝炎中起有害作用。我们进一步阐明了cDCs作为白细胞介素（IL）-12的关键来源的病理作用，IL-12可诱导自然杀伤（NK）T细胞分泌干扰素（IFN）-γ。用IL-12重建cDCs缺失的小鼠可显著恢复ConA诱导的肝炎。此外，我们确定NK T细胞是DC来源的IL-12的靶标，并且NK T细胞通过产生IFN-γ促进肝脏炎症和损伤。总之，我们的研究证明了cDCs在以IL-12依赖的方式调节NK T细胞的IFN-γ分泌从而介导ConA诱导的肝炎中的新功能。靶向cDCs可能为治疗自身免疫性肝病提供潜在的治疗应用。
