Mast Cell Regulation of Alcohol-Induced Liver Damage

酒精性肝损伤（ALD）包括多种病因，患者表现为单纯性脂肪变性

Alcoholic liver injury (ALD) encompasses a vast array of etiologies and patients present with simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma causing liver failure. Studies have examined the effects of ALD pathology on hepatocytes; however, limited information is known about the role of mast cells (MCs) and cross-talk with cholangiocytes during ALD progression. In non-alcoholic fatty liver disease (NAFLD), senescent cholangiocytes display a senescence-associated secretory phenotype (SASP), recruiting MCs to the liver where they interact with other liver cells. In patients with cholestasis and NAFLD, MCs are found in high numbers in the periportal area surrounding senescent bile ducts. Inhibition of MC-histamine (HA) ameliorates disease phenotypes. In MC-deficient mice (KitW-sh) subjected to Western Diet, there is resolution of NAFLD phenotypes. Stem cell factor (SCF) is a SASP upregulated in cholestatic patients and increased in damaged cholangiocytes during NAFLD. SCF interacts with the receptor, c-Kit, (present on MCs), and SCF/c-Kit is a prime chemoattractant pathway for MC migration. Inhibition of hepatic SCF using Vivo- Morpholino treatment decreases MC migration and cholestatic liver phenotypes in Mdr2-/- mice, and inhibition of SCF blocks MC migration toward damaged cholangiocytes, in vitro. In chronic hepatitis, MC degranulation and HA secretion are upregulated and increased SCF/c-Kit expression positively correlates to HA. Studies have demonstrated the prominent role for MCs during NAFLD and non-alcoholic steatohepatitis; however, no studies have been performed to understand the contribution of MCs or crosstalk with cholangiocytes during ALD. The premise of our exploratory study is built on preliminary data demonstrating that (i) MC presence surrounding bile ducts increases in ASH patients; (ii) in mice fed ethanol (EtOH), serum HA and SCF increase; (iii) KitW-sh mice fed EtOH have reduced hepatic steatosis and inflammation and (iv) SCF gene expression increases in cholangiocytes, but not in hepatocytes in mice fed EtOH. Based on these findings, we propose the novel hypothesis that during ALD, damaged cholangiocytes secrete increased SCF that recruits c-Kit-positive MCs to the liver promoting steatosis, ductular reaction, inflammation and fibrosis by paracrine interactions with resident liver cells and increased HA signaling. To evaluate our hypothesis, we propose the following specific aims: Specific aim 1: To demonstrate that ALD liver phenotypes are dependent on MC-HA signaling via biliary SCF and MC c-Kit interaction; and Specific aim 2: To test MC stabilizers on the progression of ALD in rodent models. We will evaluate our aims using human tissues from ALD and control and organoids built from human cells (with assistance from co-I, Dr. Burcin Ekser) along with chronic plus binge EtOH rodent models (Bin Gao-NIAAA model) with assistance from Dr. Gianfranco Alpini, collaborator. The study is both novel and exploratory, supported by preliminary data and feasible experiments. If successful, we will identify a new role for MCs along with potential therapeutic biomarkers and treatment strategies for those suffering from ALD.