IRF3 activation promotes fibrotic liver injury in alcohol-associated-liver disease

点击翻译按钮获取中文摘要

Project Summary/ Abstract Deaths from alcohol-related liver disease (ALD) are increasing due to a surge in underlying liver disease and increased alcohol consumption. ALD is a term used to describe a spectrum of diseases that range in severity. Patients with advanced disease, including fibrosis have few treatment options. Fibrosis is a disease stage indicative of transition from benign to progressive disease. Therefore, there is a clinical urgency to understand the molecular mechanism triggering fibrosis in patients with ALD to aid in the development of effective treatments strategies to curb ALD progression and improve survival. This requires an understanding of immune cell mediators responsible for modulating the dynamic interplay between liver injury and repair. Interferon regulatory factor 3 (IRF3) is a transcription factor that induces antiviral genes and is implicated in the progression of ALD. IRF3 also has non-transcriptional function involving a pro-apoptotic pathway mediated by the dsRNA binding protein (DRBP) RIG-I and IRF3 which can interact with IKKb to prevent NFkB transcription of inflammatory cytokines. Ethanol-induced stress in hepatocytes results in increased generation of dsRNA, triggering downstream inflammatory cytokine production. dsRNA originates from viral replication or host-derived sources and it functions as a damage associated molecular pattern (DAMP) to signal injury (traditionally from viral infection). Currently, the most investigated source of dsRNA accumulation in the absence of viral infection originates from the mitochondria and is associated with aberrant dsRNA degradation pathways. In the context of ALD, we predicted that dsRNA contributes to an exaggerated immune response worsening living injury and fibrosis. This may be mediated via dsRNA-induced IRF3 activation. Our lab demonstrated that Irf3-/- mice were protected from ethanol-induced liver injury, while mice expressing only non-transcriptional function of IRF3 were not protected. This non-transcriptional effect of Irf3 was driven by IRF3-mediated apoptosis of specific populations of infiltrating monocytes that resulted in worsened hepatic inflammation and contributed to ethanol- induced injury in mice. Preliminary data from this proposal demonstrates that in a chronic CCl4 fibrosis injury model, Irf3-/- mice have less fibrotic injury and increased infiltration of neutrophils, an innate immune cell population recently implicated in protection from injury. Therefore, since IRF3 modulates monocyte phenotype and increases neutrophil infiltration and dsRNA can trigger immune responses in ALD via IRF3, we hypothesize that ethanol increases dsRNA-induced IRF3 activation contributing to neutrophil infiltration and increased fibrotic liver injury associated with ALD. In this proposal, we will determine how IRF3 activation in vivo increases liver injury in an alcohol-accelerated fibrosis model and characterize in vivo knockout models dsRNA sensing response to ethanol. We will also determine the role of IRF3 in modulating neutrophil infiltration and phenotype in an alcohol-accelerated fibrosis model. Completion of these studies will contribute towards a better understanding of the crosstalk between the innate immune system and ALD-associated fibrosis.