DcR3 reprograms macrophage plasticity to promote wound healing and hair regeneration

Macrophages are key regulators of tissue repair, with M2-polarized subsets promoting anti-inflammatory, pro-regenerative functions. Decoy Receptor 3 (DcR3), a soluble TNF receptor superfamily member, modulates macrophage polarization, but its role in cutaneous regeneration remains unclear.

To elucidate the immunomodulatory role of DcR3 in macrophage polarization and evaluate its therapeutic potential in skin wound repair and hair follicle regeneration.

We employed a combination of in vitro macrophage polarization assays with in vivo models, including delayed wound healing and mechanical stretch-induced hair regeneration, to evaluate DcR3-mediated immunoregulation. Transgenic mice with macrophage-specific DcR3 overexpression were employed to investigate the physiological function of endogenous DcR3.

DcR3 accelerated wound closure and dampened pro-inflammatory gene expression in LPS-treated wounds. While physiological hair cycling remained unchanged in DcR3-transgenic mice, mechanical stimulation elicited enhanced anagen induction. In vitro, DcR3 attenuated M1 polarization while amplifying IL-4-induced M2 gene expression, thereby promoting macrophage plasticity. Adoptive transfer of DcR3-reprogrammed macrophages improved both wound healing and hair regrowth by reshaping the wound microenvironment, reducing iNOS2⁺ M1-like and increasing CD206⁺ M2-like macrophage, while enriching the transitional iNOS2⁺CD206⁺ macrophage population.

DcR3 facilitates macrophage reprogramming toward reparative phenotypes and enhances regenerative responses in skin and hair follicles, establishing DcR3 as a promising immunoregulatory target for chronic wound management and alopecia treatment.