The Monocyte to Macrophage Transition in the Murine Sterile Wound

The origin of wound repair macrophages is incompletely defined and was examined here in sterile wounds using the subcutaneous polyvinyl alcohol sponge implantation model in mice. Phenotypic analysis identified F4/80(+)Ly6C(hi)CD64(+)MerTK(–) monocytes and F4/80(+)Ly6C(low)CD64(+)MerTK(+) macrophages in the wound. Circulating monocytes were the precursors of inflammatory Ly6C(hi) wound monocytes. Ly6C(low)MerTK(+) macrophages appeared later, expressed CD206, CD11c, and MHC class II, produced cytokines consistent with repair function, and lacked a gene expression profile compatible with mesenchymal transition or fibroblastic transdifferentiation. Data also demonstrated that Ly6C(hi) wound cells were precursors of Ly6C(low) macrophages, although monocytes did not undergo rapid maturation but rather persisted in the wound as Ly6C(hi)MerTK(–) cells. MerTK-deficient mice were examined to determine whether MerTK-dependent signals from apoptotic cells regulated the maturation of wound macrophages. MerTK-deficient mice had day 14 cell compositions that resembled more immature wounds, with a smaller proportion of F4/80(+) cells and higher frequencies of Ly6G(+) neutrophils and Ly6C(hi) monocytes. The cytokine profile and number of apoptotic cells in day 14 wounds of MerTK-deficient mice was unaffected despite the alterations in cell composition. Overall, these studies identified a differentiation pathway in response to sterile inflammation in which monocytes recruited from the circulation acquire proinflammatory function, persist in the wound, and mature into repair macrophages.