Cx3CR1 Expression Identifies Distinct Macrophage Populations That Contribute Differentially to Inflammation and Repair

Abstract

Bone marrow (BM)-derived classical monocytes are critical to wound repair, where they differentiate into macrophages and purge foreign materials and dead cells while also laying the framework for tissue repair and regeneration. A subset of this recruited population persists in the wound and acquires alternative activation states to promote cell proliferation and matrix remodeling. In diabetes, this phenotypic switch is impaired and inflammation persists in an elevated state, contributing to delayed wound healing. Long-term tissue-resident macrophages can also play a key role in the resolution of inflammation to varying degrees across different organs. In this study, we investigated different macrophage subpopulations in nondiabetic and diabetic wounds over time using Cx3CR1^eGFP transgenic mice and BM transplants. We show Cx3CR1^eGFP-hi macrophages in skin wounds are derived from long-term tissue-resident macrophages and predominantly exhibit an alternative activation state, whereas cells expressing low-intermediate Cx3CR1^eGFP are derived from the BM, contribute to both early and later stages of wound healing, and show both classical and alternative activation states. Diabetic mice showed significant differences in the dynamics of these subpopulations, which likely contribute to elevated and persisting inflammatory states over time. In particular, failure of Cx3CR1^int macrophages to mature into Cx3CR1^hi links maturation to resolution of inflammation. Thus strategies to promote macrophage maturation may be effective therapeutic tools in chronic inflammatory environments.