CD44 is a key player in non-alcoholic steatohepatitis

Background & AimsCluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression.MethodsThe role of CD44 was evaluated in CD44−/− mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n = 30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n = 64) were evaluated.ResultsLiver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44−/− mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p = 0.0008) and correlated with NAFLD activity score (NAS) (p = 0.001), ballooning (p = 0.003), alanine transaminase (p = 0.005) and hepatic CCL2 (p <0.001) and macrophage marker CD68 (p <0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44+ cells. Finally, the soluble form of CD44 increased with severe steatosis (p = 0.0005) and NASH (p = 0.007).ConclusionHuman and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH.Lay summaryHuman and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy.

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