CD44 in myeloid cells: from marker to driver of chronic liver diseases.

Summary: Metabolic dysfunction associated steatotic liver disease (MASLD) and Alcohol-related liver disease (ALD) are the leading causes of severe liver disease with limited pharmacological treatments for fibrotic steatohepatitis (MASH/ASH). CD44, a glycoprotein mainly expressed in immune cells, has been implicated in multiple inflammatory diseases but never or poorly studied in ALD and MASLD context, respectively. We therefore studied its contribution to MASH/ASH development focusing on myeloid cell regulation. In MASH patients, hepatic CD44 was strongly upregulated and correlated with hepatic CCL2 and macrophage marker CD68 expression. Correction of MASH was associated with a strong decrease in liver CD44+ cells. In ALD patients, its hepatic expression increased with ALD severity and correlated with liver TNFα and CD11B expression. In mouse model of MASH and ASH, CD44 systemic or myeloid cell deficiency strongly prevented liver injury and inflammation including liver infiltration and/or activity of myeloid cells. In macrophages, CD44 deficiency enhanced the anti-inflammatory polarization and strongly decreased the activation of macrophages by lipopolysaccharide, hepatocyte damage-associated molecular patterns and saturated fatty acids. In neutrophils, CD44-deficiency reduced PMA-induced inflammatory mediator expression and increased phagocytosis of live bacteria. Finally, targeting CD44 with an antibody partially corrects ASH and NASH, making it a potential therapeutic strategy.

Biosketch: Philippe Gual is a research director in INSERM (France) and head of the team “Chronic liver diseases associated with obesity and alcohol” since 2008 at the Mediterranean Centre for Molecular Medicine (C3M) INSERM U1065 in Nice, France. He obtained his Ph.D. degree in Endocrinology at the University of Marseille, France in 1997 and his authorization to supervise research at the University of Nice Sophia Antipolis, France in 2007. His thesis (INSERM, Nice) and post-doctoral training (IRCC, Italy and then INSERM, France) focused mostly on obesity complications, insulin signaling, insulin resistance and receptor tyrosine kinases. Since 2008, his research program focuses on the better understanding of the hepatic complications associated with obesity (Metabolic dysfunction associated steatotic liver disease: MASLD) and, more recently, with chronic alcohol consumption (alcohol related liver disease, ArLD). His translational research mainly focuses on the identification and the study of markers/actors of the progression of MASLD and ArLD. He has numerous publications (in october 2024, author of 116 publications in peer-review journals and h-index 51) in Gastroenterology, J Hepatol., Hepatology, Am J Gastroenterol., Cell Mol Gastroenterol Hepatol. and Diabetes. His expertise in obesity complications is recognized as illustrated by the numerous of -invitation to review grant proposals scientific articles and structures (HCERES); -thesis supervisory committee (47), – board member of “French Association for the Study of the Liver” (2017-2019) and Inserm study section (Since 2022). -Board Member of the scientific selection committee of the International Liver Congress EASL (2021-23) and Board member of the scientific committee of UCAJEDI labex since 2022.