Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Repair

Unveiling the molecular mechanisms underlying tissue regeneration provides new opportunities to develop treatments for diabetic ulcers and other chronic skin lesions. Here, we show that Ccl2 secretion by epidermal keratinocytes is directly orchestrated by Nrf2, a prominent transcriptional regulator of tissue regeneration that is activated early after cutaneous injury. Through a unique feedback mechanism, we find that Ccl2 from epidermal keratinocytes not only drives chemotaxis of macrophages into the wound but also triggers macrophage expression of EGF, which in turn activates basal epidermal keratinocyte proliferation. Notably, we find dysfunctional activation of Nrf2 in epidermal keratinocytes of diabetic mice after wounding, which partly explains regenerative impairments associated with diabetes. These findings provide mechanistic insight into the critical relationship between keratinocyte and macrophage signaling during tissue repair, providing the basis for continued investigation of the therapeutic value of Nrf2. [Display omitted] •Epidermal Nrf2 initiates a regenerative response through Ccl2 regulation•Ccl2 release by basal stem/progenitor keratinocytes prompts macrophage trafficking•Ccl2 regulates EGF production in macrophages trafficked to the injury site•EGF from macrophages stimulates basal keratinocyte proliferation Villarreal-Ponce et al. show that diabetic wounds fail to activate Nrf2 in keratinocytes, which functions in promoting an early regenerative response in basal keratinocytes by mediating macrophage trafficking through release of Ccl2. Keratinocyte-derived Ccl2 promotes macrophage production of EGF to induce keratinocyte proliferation to promote wound repair.