Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway

Abstract

The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-α, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

“…[12][13][14][15][16]21 Our group has documented that TLR system is selectively involved in the development of hepatic IRI. 12 Indeed, the activation of TLR4, but not TLR2, was required for the induction of inflammation and hepatocellular damage in a nontransplant murine model of warm liver IRI. Furthermore, only 1 of the TLR4 downstream signaling pathways, i.e., interferon regulatory factor 3, was instrumental for triggering the disease process.…”

“…12,13 Biotinylated nucleotides were detected using streptavidin-horseradish peroxidase conjugate. Counterstaining with methyl green aids in the morphological evaluation and characterization of normal vs. apoptotic cells.…”

“…10,11 We and others have reported that TLR4 complex is involved in the initiation of IRI. [12][13][14][15][16] Indeed, we found that livers in TLR4 knockout (KO) but not TLR2 KO mice were resistant to IRI and associated intrahepatic inflammation. 12 However, our findings suggesting that TLR4 signaling plays a key role in the activation of innate immunity leading to IRI were limited to a nontransplant partial lobar warm liver ischemia model with a temporary local blood interruption.…”

“…[12][13][14][15][16] Indeed, we found that livers in TLR4 knockout (KO) but not TLR2 KO mice were resistant to IRI and associated intrahepatic inflammation. 12 However, our findings suggesting that TLR4 signaling plays a key role in the activation of innate immunity leading to IRI were limited to a nontransplant partial lobar warm liver ischemia model with a temporary local blood interruption. As both "warm" and "cold" components of the harvesting insult contribute to the pathophysiology of IRI in the clinics, much more technically demanding orthotopic liver transplants (OLTs) are required to investigate the cold IRI sequel.…”

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

“…For example, ischemia reperfusion, which results in inflammatory injury, is associated with induction of UPR target genes and XBP-1 splicing [48,49]. In the liver, damage has been shown to occur through a TLR4-mediated IRF3-dependent mechanism implicating endogenous TLR4 ligands, and raising the possibility that synergistic IFN-b induction might contribute to ischemia reperfusion injury [50]. The UPR is also activated in inflammatory myopathies, where there is evidence for an IFN-induced gene expression signature that may contribute to disease chronicity [51,52].…”