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한빛사논문, 상위피인용논문

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University of Chicago

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Autophagy, Publish online: 31 Aug 2020 | https://doi.org/10.1080/15548627.2020.1816342 Keratinocyte autophagy enables the activation of keratinocytes and fibroblasts and facilitates wound healing

Lei Qiang^1,2,3*, Seungwon Yang^1,3, Yan-Hong Cui¹, and Yu-Ying He^1*

¹Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL
60637, USA
²School of Basic Medicine and Clinical Pharmacy, State Key Laboratory of Natural
Medicines, China Pharmaceutical University, Nanjing 211198, China
³Co-first author

^*Corresponding author

Abstract

Macroautophagy/autophagy is a cellular catabolic process that is implicated in several physiological and pathological processes. However, the role of epidermal autophagy in wound healing remains unknown. Here, using mice with genetic ablation of the essential Atg5 (autophagy related 5) or Atg7 in their epidermis to inhibit autophagy, we show that keratinocyte autophagy regulates wound healing in mice. Wounding induces the expression of autophagy genes in mouse skin. Epidermis-specific autophagy deficiency inhibits wound closure, re-epithelialization, keratinocyte proliferation and differentiation, dermal granulation tissue formation, and infiltration of immune cells including macrophages, neutrophils, and mast cells, while it does not affect angiogenesis. Using cytokine array screening, we found that autophagy deficiency inhibits the transcription and production of the cytokine CCL2/MCP-1 by TNF. At the molecular level, TNF induces autophagic flux and the expression of autophagy genes through NFKB in epidermal keratinocytes. TNF promotes CCL2 transcription through the autophagy-AMPK-BRAF-MAPK/ERK-activator protein 1 (AP-1) pathway. Indeed, treating mice with recombinant CCL2 can reverse the effect of autophagy deficiency in keratinocytes. At the cellular level, we found that CCL2 induction via autophagy in keratinocytes is required not only for keratinocyte migration and proliferation but also for dermal fibroblast activation. Our findings demonstrate a critical role of epidermal autophagy in wound healing in vivo and elucidate a critical molecular machinery coordinating keratinocyte-fibroblast interaction in skin repair.

논문정보

형식Research article
게재일2020년 08월 (BRIC 등록일 2020-09-16)
연구진국외 연구진
분야 의약학 > 종양의학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2023-03-28)

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