Macrophage heterogeneity and plasticity in liver injury and repair mechanisms

Abstract

Hepatic macrophages, encompassing embryonic Kupffer cells (emKCs) and monocyte-derived macrophages (MoMFs), are recognized as important regulators of hepatic homeostasis and key players in the pathogenesis of liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging research focuses on the critical role of hepatic macrophages in mediating liver repair and regeneration following injury, where they closely interact with hepatocytes as well as hepatic stellate cells (HSCs) to regulate inflammation, fibrosis, tissue remodeling, and regeneration. The latest single-cell and spatial omics technologies have profoundly deepened our understanding of the hepatic immune response, revealing the remarkable phenotypic and spatial heterogeneity of macrophages, including distinct subsets such as lipid-associated macrophages (LAMs) within steatotic and fibrotic regions. Macrophage subsets sense systemic (e.g. gut-liver axis, adipose tissue) and local stress signals and orchestrate disease-defining cellular responses in hepatocytes, HSC, and other immune cells. Dynamic tools such as intravital microscopy have further unveiled functional properties in the spatial context hitherto unknown. Herein, we review the multifaceted roles of hepatic macrophages in liver injury and repair, with an emphasis on their role in steatosis, inflammation, fibrosis, and regeneration. We also discuss how these insights may inform the development of novel macrophage-targeted therapeutic interventions.

Keywords: Kupffer cells; MASLD; lipid-associated macrophages; liver injury; liver macrophages.