Proteomic analysis reveals a protective role of specific macrophage subsets in liver repair

Macrophages are a heterogeneous population of immune cells that play central roles in a broad range of biological processes, including the resolution of inflammation. Although diverse macrophage subpopulations have been identified, the characterization and functional specialization of certain macrophage subsets in inflamed tissues remain unclear. Here we uncovered a key role of specific macrophage subsets in tissue repair using proteomics, bioinformatics and functional analysis. We isolated two hepatic monocyte-derived macrophage subpopulations: Ly6C^hiCX₃CR1^lo macrophages and Ly6C^loCX₃CR1^hi macrophages during distinct phases of acute liver injury and employed label-free proteomics approach to profile the proteome of these cells. We found that the endocytosis- and apoptotic cell clearance-related proteins were specifically enriched in Ly6C^loCX₃CR1^hi macrophages at the resolution phase. Intriguingly, 12/15-lipoxygenase (Alox15), the most strongly up-regulated protein in Ly6C^loCX₃CR1^hi macrophages, was identified as a specific marker for these macrophages. In co-culture systems, Ly6C^loCX₃CR1^hi macrophages specifically induced hepatocyte proliferation. Furthermore, selective depletion of this population in CD11b-diphtheria toxin receptor mice significantly delayed liver repair. Overall, our studies shed light on the functional specialization of distinct macrophage subsets from different phases in the resolution of inflammation.