Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver

Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD. [Display omitted] •Resident KCs are lost with time in MAFLD•Resident KCs are replaced by distinct subsets of bone marrow derived macrophages•One subset of recruited macrophages termed hepatic LAMs, express Osteopontin•Hepatic LAMs are found in zones characterized by increased Desmin expression Hepatic macrophages are thought to play key roles in the pathogenesis of fatty liver disease; however, heterogeneity within the macrophage pool remains largely unstudied. In this issue of Immunity, Remmerie et al. report a population of osteopontin-expressing macrophages with a unique transcriptional profile and location in the fatty liver.