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

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

Cell reports (2020-11-26)
Alvaro Villarreal-Ponce, Melat Worku Tiruneh, Jasmine Lee, Christian F Guerrero-Juarez, Joseph Kuhn, Joshua A David, Kristen Dammeyer, Renee Mc Kell, Jennifer Kwong, Piul S Rabbani, Qing Nie, Daniel J Ceradini
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Macrophage Colony-Stimulating Factor from mouse, recombinant, expressed in E. coli, lyophilized powder, suitable for cell culture
Roche
KAPA2G Fast HotStart ReadyMix, 2 ×, with dye
Sigma-Aldrich
Mifepristone, ≥98%
Sigma-Aldrich
Tamoxifen, ≥99%
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, for molecular biology