Hepatic stellate cells and innate immunity in alcoholic liver disease

Abstract

Constant alcohol consumption is a major cause of chronic liver disease, and there has been a growing concern regarding the increased mortality rates worldwide. Alcoholic liver diseases (ALDs) range from mild to more severe conditions, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is enriched with innate immune cells (e.g. natural killer cells and Kupffer cells) and hepatic stellate cells (HSCs), and interestingly, emerging evidence suggests that innate immunity contributes to the development of ALDs (e.g. steatohepatitis and liver fibrosis). Indeed, HSCs play a crucial role in alcoholic steatosis via production of endocannabinoid and retinol metabolites. This review describes the roles of the innate immunity and HSCs in the pathogenesis of ALDs, and suggests therapeutic targets and strategies to assist in the reduction of ALD.

Keywords: Alcoholic liver disease; Endocannabinoid; Fibrosis; Hepatic stellate cell; Kupffer cell; Natural killer cell; Steatohepatitis; Steatosis.

Figure 1

Regulatory mechanisms of the hepatic lipogenesis and CB1 receptor expression via hepatic stellate cell-derived endocannabinoids/CB1 receptors and retinoic acid/retinoic acid receptor-γ in hepatocytes, respectively. CB1 R: CB1 receptor; AMPK: AMP-activated protein kinase; HSC: Hepatic stellate cell; 2-AG: 2-arachidonoylglycerol; SREBP-1: Sterol regulatory element-binding protein-1; FAS: Fatty acid synthase; RA: Retinoic acid; RAR: Retinoic acid receptor.

Figure 2

Mechanism of natural killer cell cytotoxicity against activated hepatic stellate cells. STAT: Signal transducer and activator of transcription; IFN: Interferon; NK: Natural killer; HSC: Hepatic stellate cell; MHC: Major histocompatibility complex; RAE1: Retinoic acid early inducible-1; RA: Retinoic acid; ADH: Alcohol dehydrogenase.

Figure 3

A model for chronic alcohol acceleration of liver fibrosis via inhibition of natural killer cell killing against hepatic stellate cells and suppressor of cytokine signaling 1 suppression of interferon-γ signaling in hepatic stellate cells. SEC: Sinusoidal endothelial cell; ADH: Alcohol dehydrogenase; HSC: Hepatic stellate cell; RA: Retinoic acid; RAE1: Retinoic acid early inducible-1; IFN: Interferon; NK: Natural killer; TGF: Transforming growth factor; SOCS1: Suppressor of cytokine signaling 1.