國家衛生研究院 NHRI:Item 3990099045/9679

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Title:	Induced expression of gasdermin A3 in the skin caused keratinocyte necrosis and anagen delay in the hair cycle
Authors:	Lin, H;Lin, P;Yang, L
Contributors:	Institute of Cellular and Systems Medicine
Abstract:	The epidermis forms a critical physical and immune barrier. Dysregulation of keratinocyte to cell death upon external stimuli could compromise the epidermal barrier immunity and cause skin inflammation. Gasdermin A was involved in gastric epithelial apoptosis; its function in the skin was hinted by the skin inflammation and hair loss phenotype in mice with dominant mutations in gasdermin A3 (Gsdma3). The mode of GSDMA3’s action and pathogenesis are in dispute. We and other group have demonstrated that N-terminal portion of Gsdma3 (N-Gsdma3) contains the functional domain, which is auto-regulated by its C-terminal domain. However, overexpression of N-Gsdma3 has been shown to induce autophagy or pyroptosis in some cell culture models. To study the biological function of GSDMA3 in vivo, we generated a doxycycline-inducible double transgenic (DTg) mouse model to express GSDMA3 in the epidermis using K14-rtTA mouse. We found that GSDMA3 overexpression caused epidermal hyperplasia and inflammatory infiltrations, which were associated with increased TNF-α and IL-1α expression. In addition, hair plucking was employed to induce hair cycle reentry at telogen phase. We found a significant delay in anagen initiation in DTg mice but their catagen phase seemed normal. We also observed increased macrophages around and in the bulge region of DTg hair follicles compared with control hair follicles, suggesting that bulge immune privilege was compromised. Regarding the underlying pathogenesis mechanism, we found increased TUNEL-positive staining and spontaneous necrotic-like keratinocytes in DTg mice. In primary keratinocytes isolated from the DTg mice, induced expression of Gsdma3 caused increased mitochondria ROS production, leakage of intracellular components, and spontaneous necrosis. Our data indicated that an innate immune-mediated mechanism could underlie the Gsdma3-mediated skin inflammation phenotype.
Date:	2016-05
Relation:	Journal of Investigative Dermatology. 2016 May;136(5, Suppl. 1):S70.
Link to:	http://dx.doi.org/10.1016/j.jid.2016.02.430
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:000380028800396
Appears in Collections:	[Liang-Tung Yang] Conference Papers/Meeting Abstract

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