Data_Sheet_1_Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis.PDF

De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways.

去新发性自身免疫性肝炎（DAIH）是肝脏移植后同种异体移植物功能障碍的重要原因，但其病因及潜在发病机制尚不明确。本研究旨在鉴定驱动 DAIH 中促炎细胞因子分泌调节性 T 细胞（Treg）表型的特定固有免疫和适应性免疫机制，并确定调节这些通路是否能够缓解 DAIH 患者肝脏中观察到的炎症环境。本研究发现，CD14++ 单核细胞中存在由 TLR2 和 4 介导的炎症小体激活，这一发现对于维持 DAIH 患者的功能障碍性 Treg 至关重要。此外，在 CD14++ 单核细胞中沉默 TLR 2 和 4 阻止了炎症小体的激活，并显著降低了 FOXP3+ Treg 的 IFN-γ 产生。我们还观察到，在具有正常同种异体移植物功能且无 DAIH 的肝脏移植受者中，肿瘤坏死因子 α 诱导蛋白 3（TNFAIP3），作为 NLRP3 炎症小体的负调节因子，其表达显著增加。而在 DAIH 患者的单核细胞/巨噬细胞中，TNFAIP3 的表达几乎不存在。我们的研究结果表明，DAIH 中的自身免疫性主要通过 CD14++ 单核细胞通过激活炎症信号通路而得到促进。