Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), represents an advanced stage of metabolic fatty liver disease, marked by liver injury and immune system involvement. TREM2+ macrophages are heavily implicated in the progression of MASH, but their specific function in the disease process has been unclear. New research identifies MS4A7, a protein enriched in macrophages, as a key factor exacerbating MASH in mice. Elevated MS4A7 expression in both human and mouse MASH correlates with liver injury severity, and knocking out the Ms4a7 gene reduced disease symptoms in male mice, suggesting it as a promising therapeutic target.
The study reveals that lipid droplets released by injured hepatocytes trigger the induction of TREM2+ macrophages, worsening liver inflammation and injury through MS4A7. Mechanistically, MS4A7 activates the NLRP3 inflammasome, a critical driver of inflammation, by directly interacting with it. This lipid droplet-MS4A7-NLRP3 inflammasome pathway plays a crucial role in MASH progression, demonstrating how macrophages contribute to the disease’s pathogenesis. The findings provide new insights into the liver’s immune microenvironment and identify potential therapeutic interventions targeting MS4A7 to mitigate MASH progression.
Reference: Zhou L, Qiu X, Meng Z, et al. Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation. Sci Transl Med. 2024 Mar 13;16(738):eadk1866. doi: 10.1126/scitranslmed.adk1866. Epub 2024 Mar 13. PMID: 38478630.
