國家衛生研究院 NHRI:Item 3990099045/9249

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Title:	Inducible expression of gasdermin A3 in the epidermis causes skin inflammation and hair cycle defect
Authors:	Lin, H;Lin, P;Yang, L
Contributors:	Institute of Cellular and Systems Medicine
Abstract:	The epidermis provides a critical barrier, which is maintained by the epidermal keratinocytes undergoing constant turnover. Gene mutations which disrupt keratincoyte proliferation, differentiation, and death are responsible for skin diseases. Gasdermin A (GSDMA) is expressed in epithelial cells of the upper gastrointestinal tract, lung, and skin; it is involved in apoptosis of the gastric epithelium cells and has been linked with asthma susceptibility in genetic association studies. The function of GSDMA in the skin remains unclear and could only be deduced from autosomal dominant mutations in gasdermin A3 (Gsdma3), an ortholog of GSDMA in mice, which caused progressive epidermal hyperplasia and alopecia. To test the hypothesis that autosomal dominance of Gsdma3 mutations are resulted from Gsdma3 gain-of-function, we generated a doxycycline-inducible double transgenic (DTg) mouse model to express GSDMA3 in the basal keratinocytes using KRT14-rtTA mouse line. We found that induced expression of Gsdma3 caused epidermal hyperplasia, inflammatory infiltrations, and hair cycle defect after depilation, which were associated with increased expression of TNF-α and IL-1α in the epidermis. These skin phenotypes are similar to those reported in Gsdma3 mutant mice. Moreover, necrotic keratinocytes and increased TUNEL-positive staining were found in the DTg epidermis. In primary keratinocytes isolated from the DTg epidermis, induced expression of Gsdma3 caused spontaneous necrosis and leakage of intracellular components with no evidence of autophagy, apoptosis, and endoplasmic reticulum stress. Our data suggest that the dominant mutations in Gsdma3 are gain-of-function mutations, and that an innate immune-mediated mechanism underlies the skin inflammation phenotype of Gsdma3 mutant strains.
Date:	2015-09
Relation:	Journal of Investigative Dermatology. 2015 Sep;135(Suppl. 2):S56.
Link to:	http://www.nature.com/jid/journal/v135/n2s/full/jid2015271a.html
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-202X&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000359739400322
Appears in Collections:	[Liang-Tung Yang] Conference Papers/Meeting Abstract

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