Innate immunity in alcoholic liver disease

Abstract

Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.

Fig. 1.

Activation of the complement system contributes the pathogenesis of alcoholic liver disease (ALD). 1: Alcohol consumption leads to an early activation of complement (C3 and C5). Activated C3a and C5a interact with their receptors on Kupffer cells, leading to TNF-α production that induces hepatocyte damage. 2: Long-term alcohol consumption activates both TLR4- and complement-dependent pathways that contribute to the pathogenesis of ALD. Adapted from Roychowdhury et al. (103) with permission.

Fig. 2.

Ethanol (EtOH) dysregulation of innate immunity contributes to the pathogenesis of ALD. Chronic alcohol consumption results in activation of innate immunity components such as Kupffer cells/LPS/TLR4 and complements or inhibition of innate immunity components such as natural killer (NK) cells, contributing to the pathogenesis of ALD. First, alcohol consumption increases gut permeability and subsequently hepatic LPS levels via binding to TLR4; LPS then stimulates Kupffer cells to produce TNF-α in a TRIF/IRF-3-dependent manner. TNF-α induces hepatocellular damage. LPS can also directly target hepatic stellate cells (HSCs) and subsequently enhance TGF-β signaling and expression of chemokines, contributing to liver fibrogenesis. Second, alcohol consumption results in activation of complement components C3a and C5a, which then stimulate Kupffer cells to produce TNF-α, contributing to hepatocellular damage. Third, alcohol consumption inhibits the antifibrotic effect of NK cells and IFN-γ via multiple steps. Alcohol inhibits NK cell functions via blocking IFN-γ and TRAIL production, inhibits IFN-γ signaling in HSCs via induction of SOCS1, and renders HSC resistance to NK cell killing via production of TGF-β that inhibits NK cell function.