Abstract
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+Ly6ChiCD64+MerTK– monocytes and F4/80+Ly6ClowCD64+MerTK+ macrophages in the wound. Circulating monocytes were the precursors of inflammatory Ly6Chi wound monocytes. Ly6ClowMerTK+ 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 Ly6Chi wound cells were precursors of Ly6Clow macrophages, although monocytes did not undergo rapid maturation but rather persisted in the wound as Ly6ChiMerTK– 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 Ly6Chi 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.
Highlights
Tissue injury induces an inflammatory response that results in the recruitment of polymorphonuclear leukocytes and monocytes to the site of damage
Differential analysis of cellular infiltrates in the sterile polyvinyl alcohol (PVA) sponge has demonstrated that monocytes are recruited to the wound within one day post-implantation, and that the frequency of monocytes/macrophages in the wound increases with time [34]
Were conducted using the subcutaneously implanted PVA sponge wound model. This model recapitulates the inflammatory, angiogenic, and fibrotic responses seen in all soft tissue wounds for at least two weeks following sponge implantation
Summary
Tissue injury induces an inflammatory response that results in the recruitment of polymorphonuclear leukocytes and monocytes to the site of damage. The order and timing by which infiltrating blood monocytes acquire macrophage traits in the sterile wound remains incompletely defined. This monocyte-to-macrophage transition was investigated using cells isolated from subcutaneously implanted polyvinyl alcohol (PVA) sponges in mice. Specific populations of blood monocytes were shown to migrate into normal skin, lungs, and lymph nodes, where they retained monocyte markers without acquiring the molecular signature of macrophages or DCs. Data to be presented indicate that monocytes migrating into a site of sterile inflammation, here an experimental wound, can either persist as monocytes with a proinflammatory phenotype or differentiate in situ to macrophages capable of producing mediators associated with repair
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