Progression of Autoimmune Hepatitis is Mediated by IL-18-Producing Dendritic Cells and Hepatic CXCL9 Expression in Mice
Progression of Autoimmune Hepatitis is Mediated by IL-18-Producing Dendritic Cells and Hepatic CXCL9 Expression in Mice
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DOI：
10.1002/hep.27087
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发表时间：
2014-07-01
期刊：
影响因子：
13.5
通讯作者：
Watanabe, Norihiko
中科院分区：
文献类型：
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作者：
Ikeda, Aki;Aoki, Nobuhiro;Watanabe, Norihiko
自身免疫性肝炎(AIH)的临床表现从轻度慢性到急性，有时是暴发性肝炎。然而，目前尚不清楚如何进展为致命性肝炎。我们通过诱导叉头盒P3(+)调节性T细胞的同时丢失和程序性细胞死亡-1(PD-1)介导的信号转导，建立了致死性AIH的小鼠模型。在这个模型中，脾中调节失调的滤泡辅助T细胞负责诱导，而C-C趋化因子受体6/C-C趋化因子配体20轴是这些T细胞向肝脏迁移的关键。利用这一致命性AIH模型，我们旨在阐明触发致命性AIH进展的关键分子。在炎症过程中，T-bet、干扰素(IFN)-γ和C-X-C趋化因子受体(CXCR)3在炎症肝脏中高表达，提示辅助性T(Th)1型炎症。主要在脾和炎症肝脏中扩张的T细胞是表达CXCR3的CD8(+)T细胞；这些CD8(+)T细胞的耗尽抑制了AIH的进展。CXCR3的一种配体，趋化因子(C-X-C基序)配体(CXCL)9在肝脏中的表达增加。表达CXCL9的巨噬细胞/Kupffer细胞与浸润性T细胞共定位，体内应用抗CXCL9可抑制AIH的进展。此外，在疾病进展过程中，血清IL-18水平升高，但IL-1β水平不升高，脾和肝脏中的树突状细胞高度产生IL-18。体内应用抗IL-18R可抑制脾CXCR3(+)T细胞的增加和向致死性AIH的进展。此外，肿瘤坏死因子α，而不是干扰素-γ，参与了肝脏CXCL9的上调和血清IL-18水平的升高。结论：在我们的小鼠模型中，AIH的致命性进展是由IL-18依赖的T细胞向Th1细胞和效应T细胞的分化所介导的，而CXCR3-CXCL9轴依赖的T细胞的迁移在致命性进展中是至关重要的。
Clinical manifestations of autoimmune hepatitis (AIH) range from mild chronic to acute, sometimes fulminant hepatitis. However, it is unknown how the progression to fatal hepatitis occurs. We developed a mouse model of fatal AIH by inducing a concurrent loss of forkhead box P3(+) regulatory T cells and programmed cell death-1 (PD-1)-mediated signaling. In this model, dysregulated follicular helper T cells in the spleen are responsible for the induction, and the C-C chemokine receptor 6/C-C chemokine ligand 20 axis is crucial for the migration of these T cells into the liver. Using this fatal AIH model, we aimed to clarify key molecules triggering fatal AIH progression. During progression, T-bet together with interferon (IFN)-gamma and C-X-C chemokine receptor (CXCR)3 were highly expressed in the inflamed liver, suggesting helper T (Th)1-type inflammation. T cells that dominantly expanded in the spleen and the inflamed liver were CXCR3-expressing CD8(+) T cells; depletion of these CD8(+) T cells suppressed AIH progression. Expression of one CXCR3 ligand, chemokine (C-X-C motif) ligand (CXCL) 9, was elevated in the liver. CXCL9-expressing macrophages/Kupffer cells were colocalized with infiltrating T cells, and in vivo administration of anti-CXCL9 suppressed AIH progression. In addition, serum levels of interleukin (IL)-18, but not IL-1 beta, were elevated during progression, and dendritic cells in the spleen and liver highly produced IL-18. In vivo administration of anti-IL-18R suppressed the increase of splenic CXCR3(+) T cells and the progression to fatal AIH. Moreover, tumor necrosis factor alpha, but not IFN-gamma, was involved in up-regulating CXCL9 in the liver and for increased serum levels of IL-18. Conclusion: These data suggest that, in our mouse model, fatal progression of AIH is mediated by IL-18-dependent differentiation of T cells into Th1 cells and effector T cells, respectively, and that CXCR3-CXCL9 axis-dependent migration of those T cells is crucial for fatal progression.