CD24 regulates liver immune response and ameliorates acute hepatic injury through controlling hepatic macrophages

Liver injury releases danger‐associated molecular patterns, which trigger the immune response. CD24 negatively regulates the immune response by binding with danger‐associated molecular patterns, but the specific role of CD24 in modulating macrophage‐related inflammation during liver injury remains largely unexplored. Here, we aimed to investigate the mechanisms of macrophage CD24 in the development of liver injury. Our results show that CD24 expression is upregulated primarily in hepatic macrophages (HMs) during acute liver injury. CD24‐deficient mice exhibited more severe liver injury and showed a significantly higher frequency and number of HMs, particularly Ly6Chi monocyte‐derived macrophages. Mechanistically, the CD24‐Siglec‐G interaction plays a vital role in mitigating acute liver injury. CD24‐mediated inhibitory signaling in HMs primarily limits downstream NF‐κB and p38 MAPK activation through the recruitment of SHP1. Our work unveils the critical role of macrophage CD24 in negatively regulating innate immune responses and protecting against acute liver injury, thus providing potential therapeutic targets for liver‐associated diseases. CD24 on hepatic macrophages limits liver injury by interacting with Siglec‐G and inhibiting inflammatory pathways. CD24 deficiency exacerbates liver damage, underscoring its potential as a therapeutic target for liver diseases.