Macrophages Promote Wound-Induced Hair Follicle Regeneration in a CX3CR1-and TGF-β1-Dependent Manner

Hair follicle stem cells are regulated by intrafollicular and extrafollicular niche signals. Appropriate hair follicle regeneration relies on the coordinated release and integration of these signals. How immune cells, particularly cutaneous macrophages, influence the hair follicle stem cell niche and regeneration is not well understood. We took advantage of wound-induced hair growth (WIHG) to explore the relationship between wound macrophages and hair follicle regeneration. First, we showed that WIHG is dependent on CD11b(+)F4/80(+) macrophages at 7-11 days after injury. Next, using CX(3)CR1(gfp/+):CCR2(rfp/+) mice to capture the dynamic spectrum of macrophage phenotypes during wound healing, we showed that wound macrophages transition from a CX(3)CR1(lo/med) to a CX(3)CR1(hi) phenotype at the onset of WIHG. Finally, WIHG is abolished in mice deficient for CX(3)CR1, delayed with pharmacological inhibition of transforming growth factor-beta receptor type 1, and rescued with exogenous transforming growth factor-beta 1. Overall, we propose a model in which transforming growth factor-b1 and CX(3)CR1 are critical for recruiting and maintaining the CCR2(+)CX(3)CR1(hi)Ly6C(lo)TNF alpha(+) macrophages critical for stimulating WIHG.