IL-36α Promoted Wound Induced Hair Follicle Neogenesis via Hair Follicle Stem/Progenitor Cell Proliferation

Abstract

Background Wound-induced hair follicle neogenesis (WIHN) is a phenomenon of hair neogenesis that occurs at the center of a scar when the wound area is sufficiently large. Neogenic hair follicles are separated from the pre-existing follicles at the wound edge by a hairless circular region. This WIHN study provides a unique model for developing treatments for hair loss and deciphering the mechanisms underlying organogenesis in adult mammals. Methods The skin of a mouse was wounded by excising a 1.5 × 1.5 cm 2 square of full-thickness dorsal skin. iTRAQ technology was used to screen proteins differentially expressed between the inner and outer scar areas in a mouse model of WIHN, on post-wounding day 15, to identify the regulators of WIHN. Owing to the overexpression of interleukin-36α (IL-36α) in the de novo hair follicle growth area, the regulating effect of IL-36α overexpression in WIHN was investigated. Hair follicle stem/progenitor cells were counted by flow cytometry while the expression of hair follicle stem/progenitor cell markers ( Lgr5, Lgr6, Lrig1, K15 , and CD34 ) and that of Wnt/β-catenin and IL-6/STAT3 pathway intermediaries was detected by qPCR and western blotting. Results We found that wounding induced IL-36α expression. Incorporation of recombinant murine IL-36α (mrIL-36α) into murine skin wounds resulted in a greater number of regenerated hair follicles ( p < 0.005) and a faster healing rate. The expression of hair follicle stem/progenitor cell markers was upregulated in the mrIL-36α-injected site ( p < 0.05). Additionally, mrIL-36α upregulated the IL-6/STAT3 pathway intermediaries. Conclusion IL-36α is upregulated in de novo hair follicle growth areas and can promote wound epithelialization and WIHN.

Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism

“…However, a recent study showed that obesity accelerates hair depletion through IL-1R signaling ( 51 ), likely reflecting a difference in the response to IL-1β in the context of regeneration versus homeostatic maintenance. Similar to our findings, paralog IL-1α has been shown to activate HFSCs and up-regulate IL-36α and IL-6 to promote WIHN ( 26 , 52 , 53 ). Together, the evidence suggests that IL-1 signaling is a powerful proregenerative cue in response to skin damage.…”

Wound Induced Hair Neogenesis – A Novel Paradigm for Studying Regeneration and Aging

“…In summary, TLR activation in response to wounding leads to IL-6 production and STAT3 phosphorylation, activating a STAT3-dependent gene expression program to promote WIHN. This conclusion agrees with recent studies that have characterized other IL-6 type molecules such as IL-36α that activate STAT3 and induce WIHN (Gong et al, 2020). Strikingly, the same IL-6/STAT3 pathway that governs WIHN is implicated in impaired cutaneous wound healing in aged mice.…”

STAT3 Partly Inhibits Cell Proliferation via Direct Negative Regulation of FST Gene Expression

“…STAT3 belongs to the signal transduction and transcription activation factor family in cell signal activation and transduction ( Kong et al, 2019 ). It has been shown that STAT3 plays a vital role in the hair follicle and morphogenesis and development ( Sano et al, 2008 ; Yu et al, 2014 ; Nelson et al, 2015 ; Gong et al, 2018 , 2020 ). Whether STAT3 regulates FST is not clear.…”