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 (Mcbs) and its possible influence on the inflammatory microenvironment that may lead to NAFLD. TM4SF5 induction in differentiated Mcbs promotes glucose uptake, glycolysis, and glucose sensitivity, leading to M1-type Mcb activation. Activated M1-type Mcbs 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 Mcbs, further chronic exposure reprograms Mcbs for an increase in the proportion of M2-type Mcbs in the population, which may support diet-and chemical-induced NAFLD progression. We suggest that TM4SF5 expression in Mcbs and hepatocytes is critically involved in modulating the inflammatory environment during NAFLD progression.