CD44 in Group 1 Innate Lymphoid Cells Impacts the Development and Progression of Steatohepatitis

ABSTRACT Background and Aims Innate lymphoid cells (ILCs) play pivotal roles in inflammation and fibrosis, which are key features of chronic liver diseases. The contribution of group 1 ILCs, including natural killer (NK) cells and helper‐like ILC1s, to liver inflammation during steatohepatitis and metabolic dysfunction‐associated steatotic liver diseases (MASLD) is still a matter of debate and requires further investigation. Methods We engineered a mouse model of specific deficiency of CD44 in group 1 ILCs and challenged mice with diet‐induced obesity and MASLD or diet‐induced steatohepatitis. We performed in vitro studies and co‐cultured LPS‐stimulated liver NK cells with hepatocytes and macrophages to analyse the inflammatory response. Results As group 1 ILCs expressed the cell surface molecule CD44, its specific targeting was used to investigate if CD44 could affect the development of liver inflammation. Here, we found that CD44 deficiency in group 1 ILCs was sufficient to decrease the absolute number of hepatic NKp46 + ILCs, NK cells and ILC1s in chow diet and in response to diet induced‐MASLD or steatohepatitis. CD44 deficiency in group 1 ILCs aggravated liver complications by exacerbating hepatic injury, inflammation, and fibrosis, which was also associated with inflammatory and osteopontin + macrophages accumulation. The absence of CD44 in NK cells enhanced their inflammatory phenotypes in response to LPS, which in turn triggered release of pro‐inflammatory mediators by hepatocytes and macrophages. Conclusions Our findings reveal a novel role for CD44 in regulating the dynamics of group 1 ILCs, which in turn affects steatohepatitis and MASLD development.