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

Abstract

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.

IL-18 and IL-1β Gene Polymorphisms: The Plausible Risk Factors for Chronic Hepatitis B

“…Interestingly, both IL-18 and IL-1b receptors contain a toll-IL-1 receptor (TIR) domain, which is common with TIR domain of TLRs and, hence, the intracellular signaling pathways of TLRs and IL-8/IL-1b receptors are similar and associated with activation of several TFs such as nuclear factor kappa-light-chain-enhancer of activated B cells, interferon regulatory factor 7, and activator protein-1 in the signaling adaptor myeloid differentiation primary response 88-dependent manner (16). It appears that IL-18/IL-1b in-teractions with their corresponded receptors lead to activation of intracellular signaling pathways, which have synergistic effects with TLR signaling pathways (4). The functions of IL-18 and IL-1b can be regulated by IL-18 binding protein and IL-1 receptor antagonist, respectively (10,14).…”

“…Inflammasomes are a set of intracellular innate immune receptors, which recognize intracellular PAMPs and damage associated molecular patterns (47). They also are activated by other innate immune receptors such as toll-like receptors (TLRs), which are entitled inflammasome priming (4).…”

Role of deleterious single nucleotide variants in the coding regions of TNFAIP3 for Japanese autoimmune hepatitis with cirrhosis

“…TNFAIP3 encodes A20, an inhibitor of the NF-κB signaling pathway, and is a susceptibility gene for autoimmune diseases and HA20 14–17,20–23 . A20 is a negative regulator of the NLRP3 inflammasome and plays some important roles against autoimmune diseases 18,19 . TNIP1 is a predisposing gene in AIH 12 , and encodes an adaptor protein binding to A20.…”

“…A20 is a negative regulator of the NLRP3 inflammasome and myeloid cell specific deletion of A20 caused spontaneous arthritis in mice 18 . Analogically, inflammasome was activated in monocytes of non-transplanted AIH children and liver-transplanted children with de novo autoimmune hepatitis, but increased expression of A20 was observed in monocytes of liver-transplanted children without de novo autoimmune hepatitis 19 . Thus, A20 plays some important roles against autoimmune diseases.…”

NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases

“…Another class of PRRs important for the regulation of inflammasomes is the Toll-like receptors (TLRs) [ 19 , 20 ]. TLRs are type-I integral membrane receptors [ 21 ].…”