PDF(Pubmed)
Abstract：
Homeostasis of the skin barrier is essential for maintaining normal skin function. Gasdermin A (GSDMA) is highly expressed in the skin and associated with many skin diseases, such as melanoma and psoriasis. In mice, GSDMA is encoded by three gene homologues, namely Gsdma1, Gsdma2, and Gsdma3. Although Gsdma3 gain-of-function mutations cause hair loss and skin inflammation, Gsdma3-deficient mice do not show any visible phenotypes in skin and hair structures. To explore the physiological function of GSDMA, we generated conventional Gsdma1/2/3 knockout (KO) mice. These mice showed significantly alleviated epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate (PMA). Furthermore, the alleviation of epidermal hyperplasia depended on the expression of Gsdma1/2/3 specifically in keratinocytes. Mechanistically, Gsdma1/2/3 depletion downregulated epidermal growth factor receptor (EGFR) ligands, leading to the decreased EGFR-Stat3/Akt signalling. These results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR-Stat3/Akt pathway.
摘要：
皮肤屏障的稳态对于维持正常皮肤功能至关重要。GasderminA（GSDMA）在皮肤中高表达，与许多皮肤病有关。如黑色素瘤和牛皮癣。在老鼠身上,GSDMA由三个基因同源物编码,即Gsdma1、Gsdma2和Gsdma3。尽管Gsdma3功能获得突变会导致脱发和皮肤炎症，Gsdma3缺陷型小鼠在皮肤或毛发结构中没有显示表型。探讨GSDMA的生理功能,我们产生了常规Gsdma1/2/3敲除（KO）小鼠。我们发现Gsdma1/2/3KO小鼠显示出由佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的表皮增生和炎症显着降低。此外，我们发现表皮增生的缓解依赖于角质形成细胞特异性表达的Gsdma1/2/3。机械上,Gsdma1/2/3耗竭下调表皮生长因子受体（EGFR）配体，导致EGFR-Stat3/Akt信号降低。这些结果表明Gsdma1/2/3的消耗通过抑制EGFR-Stat3/Akt途径部分地减轻了PMA诱导的表皮增生。
