Murine macrophage chemokine receptor CCR2 plays a crucial role in macrophage recruitment and regulated inflammation in wound healing

Abstract

Macrophages play a critical role in the establishment of a regulated inflammatory response following tissue injury. Following injury, CCR2⁺ monocytes are recruited from peripheral blood to wound tissue, and direct the initiation and resolution of inflammation that is essential for tissue repair. In pathologic states where chronic inflammation prevents healing, macrophages fail to transition to a reparative phenotype. Using a murine model of cutaneous wound healing, we found that CCR2-deficient mice (CCR2^-/- ) demonstrate significantly impaired wound healing at all time points postinjury. Flow cytometry analysis of wounds from CCR2^-/- and WT mice revealed a significant decrease in inflammatory, Ly6C^Hi recruited monocyte/macrophages in CCR2^-/- wounds. We further show that wound macrophage inflammatory cytokine production is decreased in CCR2^-/- wounds. Adoptive transfer of mT/mG monocyte/macrophages into CCR2^+/+ and CCR2^-/- mice demonstrated that labeled cells on days 2 and 4 traveled to wounds in both CCR2^+/+ and CCR2^-/- mice. Further, adoptive transfer of monocyte/macrophages from WT mice restored normal healing, likely through a restored inflammatory response in the CCR2-deficient mice. Taken together, these data suggest that CCR2 plays a critical role in the recruitment and inflammatory response following injury, and that wound repair may be therapeutically manipulated through modulation of CCR2.

Keywords: Chemokine receptor; Inflammation; Macrophages; Recruitment; Wound healing.