CD44 in myEloid cells is a major driver of liver inflammation and injury in alcohol-related liver disease

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BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) is one of the leading causes of severe liver disease with limited pharmacological treatments for alcohol-associated steatohepatitis. CD44, a glycoprotein mainly expressed in immune cells, has been implicated in multiple inflammatory diseases but has never been studied in the ALD context. We therefore studied its contribution to alcohol-associated steatohepatitis development in mice and its expression in patients with ALD. APPROACH AND RESULTS: Here, we report that liver CD44 expression is associated with liver injury and inflammation and its deficiency ( Cd44-/- ) partially protected mice on chronic plus binge ethanol feeding. CD44 deletion in myeloid cells ( Cd44myel-KO ) recapitulated the same protective effects associated with reduced inflammatory monocyte infiltration and neutrophil activation in the liver and diminished blood neutrophil-lymphocyte ratio. CD44-deficient neutrophils displayed reduced phorbol 12-myristate 13-acetate-induced inflammatory mediator expression and increased phagocytosis of live bacteria. Cd44myel-KO mice were also protected against hepatic steatosis mediated by chronic plus binge ethanol feeding or chronic ethanol feeding due in part to increased SIRT1-mediated fatty acid beta-oxidation. CD44 neutralization with antibodies strongly decreased liver injury and inflammation (hepatic neutrophil frequency) and blood neutrophil-lymphocyte ratio on chronic plus binge ethanol feeding. In samples from patients with ALD, hepatic CD44 expression increased with ALD severity, correlated with hepatic TNFα and CD11b expression, and CD44-expressing neutrophils were enriched in alcohol-associated hepatitis. CONCLUSIONS: Human and experimental evidence supports CD44 as a marker of hepatic inflammation in ALD. In addition, CD44 modulates neutrophil mobilization and functions, and its targeting partially prevents liver inflammation and injury in the context of acute-on-chronic alcohol drinking.

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