CD44 in myeloid cells is a major driver of liver inflammation and injury in alcohol-associated liver disease.

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.