TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment

Chronic injury to hepatocytes results in inflammation, steatohepatitis, fibrosis, and nonalcoholic fatty liver disease (NAFLD). The tetraspanin TM4SF5 is implicated in fibrosis and cancer. We investigate the role of TM4SF5 in communication between hepatocytes and macrophages (MΦs) and its possible influence on the inflammatory microenvironment that may lead to NAFLD. TM4SF5 induction in differentiated MΦs promotes glucose uptake, glycolysis, and glucose sensitivity, leading to M1-type MΦ activation. Activated M1-type MΦs secrete pro-inflammatory interleukin-6 (IL-6), which induces the secretion of CCL20 and CXCL10 from TM4SF5-positive hepatocytes. Although TM4SF5-dependent secretion of these chemokines enhances glycolysis in M0 MΦs, further chronic exposure reprograms MΦs for an increase in the proportion of M2-type MΦs in the population, which may support diet- and chemical-induced NAFLD progression. We suggest that TM4SF5 expression in MΦs and hepatocytes is critically involved in modulating the inflammatory environment during NAFLD progression. [Display omitted] •Nonalcoholic fatty liver disease (NAFLD) involves chronic inflammatory remodeling•TM4SF5 regulates a bidirectional communication between hepatocytes and macrophages•TM4SF5-mediated remodeling of inflammatory macrophages can promote NASH phenotypes Kim et al. show that, during development of nonalcoholic fatty liver disease (NAFLD), TM4SF5 mediates crosstalk between hepatocytes and macrophages to remodel the inflammatory environment. TM4SF5-dependent communication involves hepatic CCL20/CXCL10 and macrophagic IL-6 secretion, resulting in activation of pro-inflammatory macrophages that could be chronically reprogrammed to be pro-fibrotic for NAFLD progression.