Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair

Our understanding of the functional heterogeneity of resident versus recruited macrophages in the diseased liver is limited. A population of recruited lipid-associated macrophages (LAMs) has been reported to populate the diseased liver alongside resident Kupffer cells (KCs). However, the precise roles of these distinct macrophage subsets remain elusive. Here, using proteogenomics, we have identified LAMs in multiple models of liver injury. Moreover, we found that this phenotype is not specific to recruited macrophages, as a subset of resident KCs can also adopt a LAM-like phenotype in the mouse and human liver. By combining genetic mouse models targeting the distinct populations, we determined that both recruited LAMs and resident LAM-like KCs play crucial roles in tissue repair. Specifically, triggering receptor expressed on myeloid cells 2 (TREM2) expression on either resident or recruited macrophages is required for the efficient clearance of dying cells, enhancing repair and preventing exacerbated fibrosis.