956 Epidermal autophagy deficiency impairs skin wound healing through inhibiting keratinocyte proliferation and migration and fibroblast activation

Abstract

Macroautophagy (hereafter autophagy) is a cellular catabolic process that is implicated in many physiological and pathological processes. However, the role of autophagy in skin wound healing is unknown. Here we show that epidermal autophagy deficiency impairs wound healing in mice. Epidermis-specific deletion of the autophagy essential genes Atg5 or Atg7 inhibited wound healing in mice. Epidermal autophagy deficiency inhibited wound closure, re-epithelialization, dermal granulation tissue formation, and inflammatory immune cell infiltration. Using cytokine array screening, we identified that autophagy deficiency inhibits the transcription and production of the cytokine MCP-1 (monocyte chemoattractant protein-1) viaTNF-a(tumor necrosis factor-alpha), a cytokine generated at the early stage of wound response. Furthermore, TNF-ainduced autophagy in epidermal keratinocytes. At the molecular level, TNF-a-induced autophagy promoted MCP-1 transcription through the ERK/AP-1 pathway at the AP-1 binding site of the MCP-1 promoter in keratinocytes. Furthermore, we found that autophagy promotes ERK phosphorylation through regulating the AMPK/BRAF phosphorylation signaling axis. Treatment with recombinant MCP-1 increased wound repair, reversing the wound healing phenotype in mice with epidermal autophagy deficiency. At the cellular level, we found that autophagy-mediated MCP-1 induction in keratinocytes is required not only for keratinocyte migration, but also for dermal fibroblast activation. Our findings demonstrate a critical role of epidermal autophagy in wound healing, and elucidated new molecular machineries coordinating the keratinocyte-fibroblast interaction, and may provide new opportunities by targeting the autophagy pathways to improve wound repair in affected individuals with defects in wound healing.