Gasdermin A Is Required for Epidermal Cornification during Skin Barrier Regeneration and in an Atopic Dermatitis-Like Model

Li Ying Huang, Shao Ting Li, Shiang Chi Lin, Cheng Heng Kao, Chien Hui Hong, Chih Hung Lee, Liang Tung Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

6 Scopus citations

Abstract

Atopic dermatitis is featured with impaired skin barrier. The stratum corneum and the intercellular tight junctions constitute the permeability barrier, which is essential to protect water loss in the host and prevent pathogen entry. The epidermal barrier is constantly renewed by differentiating keratinocytes through cornification, during which autophagy contributes to elimination of organelles and nucleus. The human GSDMA and its mouse homologs Gsdma1–3 are expressed in the suprabasal epidermis. Although a pyroptotic role of GSDMA/Gsdma1 in host defense against Streptococcus pyogenes has been reported, the physiological function of Gsdma1/a2/a3 in epidermal homeostasis remains elusive. Here, through repeated epidermal barrier disruption, we found that tight junction formation and stratum corneum maturation were defective in the Gsdma1/a3-deficient epidermis. Using comparative gene profiling analysis, mitochondrial respiration measurement, and in vivo tracing of mitophagy, our data indicate that Gsdma1/a3 activation leads to mitochondrial dysfunction and subsequently facilitates mitochondrial turnover and epidermal cornification. In calcipotriol (MC903)-induced atopic dermatitis-like animal model, we showed that Gsdma1/a3-deficiency selectively enhanced the T helper type 2 response. Remarkably, the GSDMA expression is reduced in the epidermis of patients with atopic dermatitis compared with that of normal individuals. Gsdma1/a3-deficiency might be involved in atopic dermatitis pathogenesis, likely through GSDMA-mediated epidermal differentiation and cornification.

Original languageEnglish
Pages (from-to)1735-1745.e11
JournalJournal of Investigative Dermatology
Volume143
Issue number9
DOIs
StatePublished - 09 2023

Bibliographical note

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords

  • Humans
  • Animals
  • Mice
  • Dermatitis, Atopic/pathology
  • Gasdermins
  • Epidermis/pathology
  • Keratinocytes/metabolism
  • Regeneration
  • Pore Forming Cytotoxic Proteins/metabolism

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