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

• Published in: Frontiers in immunology Vol. 9; p. 1612
• Main Authors: Arterbery, Adam S, Yao, Jie, Ling, Andrew, Avitzur, Yaron, Martinez, Mercedes, Lobritto, Steven, Deng, Yanhong, Geliang, Gan, Mehta, Sameet, Wang, Guilin, Knight, James, Ekong, Udeme D
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 19-07-2018
• Subjects: CD14++ monocytes; Immunology; inflammasome; innate immunity; liver transplantation; Th1 regulatory T cells; toll-like receptors; CD14++ monocytes; autoimmune hepatitis; innate immunity; toll-like receptors; tumor necrosis factor α-induced protein 3; inflammasome; Th1 regulatory T cells; liver transplantation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.01612

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 (
), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH.
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.