The 17q12-21 locus harboring ORMDL sphingolipid biosynthesis regulator 3(ORMDL3)and Gasdermin B(GSDMB)genes exhibits one of the most significant and replicated associations with asthma[MIM:600807](Stein et al.,2018).S...The 17q12-21 locus harboring ORMDL sphingolipid biosynthesis regulator 3(ORMDL3)and Gasdermin B(GSDMB)genes exhibits one of the most significant and replicated associations with asthma[MIM:600807](Stein et al.,2018).Several studies explored the complex interactions between SNPs,gene expression and epigenetic modifications at this locus,primarily focusing on the levels of expressed ORMDL3 and GSDMB(Stein et al.,2018).Given that DNA methylation and gene expression signals are cell-type specific(Reinius et al.,2012),isolated materials such as lymphocytes from blood and,to a lesser extent,bronchial epithelial cells from biopsies of bronchi or bronchoalveolar lavages have been used in a number of studies to investigate such interactions(Stein et al.,2018).展开更多
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 i...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.展开更多
基金supported by operating grants from the Canadian Institute of Health Research(CIHR awards 133605 and 141900Laprise&Pastinen)provided by the Wellcome Trust under award WT091310。
文摘The 17q12-21 locus harboring ORMDL sphingolipid biosynthesis regulator 3(ORMDL3)and Gasdermin B(GSDMB)genes exhibits one of the most significant and replicated associations with asthma[MIM:600807](Stein et al.,2018).Several studies explored the complex interactions between SNPs,gene expression and epigenetic modifications at this locus,primarily focusing on the levels of expressed ORMDL3 and GSDMB(Stein et al.,2018).Given that DNA methylation and gene expression signals are cell-type specific(Reinius et al.,2012),isolated materials such as lymphocytes from blood and,to a lesser extent,bronchial epithelial cells from biopsies of bronchi or bronchoalveolar lavages have been used in a number of studies to investigate such interactions(Stein et al.,2018).
基金supported by grants from the Ministry of Science and Technology of China(2018YFA0801100 and 2021YFF0702100)the National Natural Science Foundation of China(31971056,31772550,and 32000513)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20181260)the Fundamental Research Funds for the Central Universities(14380516 and 021414380533).
文摘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.
