Context-Dependent Roles of Liver Macrophages in MASH

Metabolic dysfunction-associated steatohepatitis is a consequence of pathological hepatocellular lipid accumulation where lipotoxic stress triggers chronic inflammation. Liver macrophages are important regulators in the transition from simple steatosis to steatohepatitis and progression toward fibrosis, cirrhosis, and hepatocellular carcinoma. In this process, the hepatic macrophage pool undergoes a significant transformation with loss of embryonic Kupffer cells (KCs) and infiltration of diverse subsets of monocyte-derived macrophages, including monocytic KCs and lipid-associated macrophages (LAMs). Emerging evidence supports macrophage infiltration and the emergence of LAMs as primary adaptive responses aimed at restoring tissue homeostasis by mitigating lipotoxic stress, clearing cell death signals, and promoting the resolution of steatohepatitis and fibrosis regression. Chronic exposure of LAMs to lipotoxic and inflammatory conditions, however, induces inflammatory and fibrogenic programs that drive steatohepatitis and fibrosis progression. In conclusion, these context-dependent roles of liver macrophage subsets have important therapeutic implications, supporting approaches to shift macrophages toward tissue-restoring responses.