PDF(Pubmed)
Abstract：
UNASSIGNED: Recent studies have shown that activated pyroptosis in atopic dermatitis (AD) switches inflammatory processes and causes abnormal cornification and epidermal barrier dysfunction. Little research has focused on the interaction mechanism between pyroptosis-related genes and human keratinocyte differentiation.
UNASSIGNED: The AD dataset from the Gene Expression Omnibus (GEO) was used to identify differently expressed pyroptosis-related genes (DEPRGs). Hub genes were identified and an enrichment analysis was performed to select epithelial development-related genes. Lesions of AD patients were detected via immunohistochemistry (IHC) to verify the hub gene. Human keratinocytes cell lines, gasdermin D (GSDMD) overexpression, Caspase1 siRNA, Histone Deacetylase1 (HDAC1) siRNA, and HDAC1 overexpression vectors were used for gain-and-loss-of-function experiments. Regulation of cornification protein was determined by qPCR, western blot (WB), immunofluorescence (IF), dual-luciferase reporter assay, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP).
UNASSIGNED: A total of 27 DEPRGs were identified between either atopic dermatitis non-lesional skin (ANL) and healthy control (HC) or atopic dermatitis lesional skin (AL) and HC. The enrichment analysis showed that these DEPRGs were primarily enriched in the inflammatory response and keratinocytes differentiation. Of the 10 hub genes identified via the protein-protein interaction network, only GSDMD was statistically and negatively associated with the expression of epithelial tight junction core genes. Furthermore, GSDMD was upregulated in AD lesions and inhibited human keratinocyte differentiation by reducing filaggrin (FLG) expression. Mechanistically, GSDMD activated by Caspase1 reduced FLG expression via HDAC1. HDAC1 decreased FLG expression by reducing histone acetylation at the FLG promoter. In addition, GSDMD blocked the interaction of Potassium Channel Tetramerization Domain Containing 6 (KCTD6) and HDAC1 to prohibit HDAC1 degradation.
UNASSIGNED: This study revealed that GSDMD was upregulated in AD lesions and that GSDMD regulated keratinocytes via epigenetic modification, which might provide potential therapeutic targets for AD.
UNASSIGNED: The AD dataset from the Gene Expression Omnibus (GEO) was used to identify differently expressed pyroptosis-related genes (DEPRGs). Hub genes were identified and an enrichment analysis was performed to select epithelial development-related genes. Lesions of AD patients were detected via immunohistochemistry (IHC) to verify the hub gene. Human keratinocytes cell lines, gasdermin D (GSDMD) overexpression, Caspase1 siRNA, Histone Deacetylase1 (HDAC1) siRNA, and HDAC1 overexpression vectors were used for gain-and-loss-of-function experiments. Regulation of cornification protein was determined by qPCR, western blot (WB), immunofluorescence (IF), dual-luciferase reporter assay, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP).
UNASSIGNED: A total of 27 DEPRGs were identified between either atopic dermatitis non-lesional skin (ANL) and healthy control (HC) or atopic dermatitis lesional skin (AL) and HC. The enrichment analysis showed that these DEPRGs were primarily enriched in the inflammatory response and keratinocytes differentiation. Of the 10 hub genes identified via the protein-protein interaction network, only GSDMD was statistically and negatively associated with the expression of epithelial tight junction core genes. Furthermore, GSDMD was upregulated in AD lesions and inhibited human keratinocyte differentiation by reducing filaggrin (FLG) expression. Mechanistically, GSDMD activated by Caspase1 reduced FLG expression via HDAC1. HDAC1 decreased FLG expression by reducing histone acetylation at the FLG promoter. In addition, GSDMD blocked the interaction of Potassium Channel Tetramerization Domain Containing 6 (KCTD6) and HDAC1 to prohibit HDAC1 degradation.
UNASSIGNED: This study revealed that GSDMD was upregulated in AD lesions and that GSDMD regulated keratinocytes via epigenetic modification, which might provide potential therapeutic targets for AD.
摘要：
■最近的研究表明，特应性皮炎（AD）中激活的焦凋亡会切换炎症过程，并导致异常的角化和表皮屏障功能障碍。很少有研究关注焦亡相关基因与人角质形成细胞分化之间的相互作用机制。
■来自基因表达综合(GEO)的AD数据集用于鉴定不同表达的焦亡相关基因(DEPRG)。鉴定Hub基因并进行富集分析以选择上皮发育相关基因。通过免疫组织化学（IHC）检测AD患者的病变以验证hub基因。人角质形成细胞系,gasderminD(GSDMD)过表达,Caspase1siRNA,组蛋白去乙酰化酶1(HDAC1)siRNA,和HDAC1过表达载体用于功能获得和丧失实验。通过qPCR确定角质化蛋白的调节，蛋白质印迹(WB),免疫荧光（IF），双荧光素酶报告分析，免疫共沉淀（Co-IP），和染色质免疫沉淀(ChIP)。
■在特应性皮炎非病灶性皮肤(ANL)和健康对照(HC)或特应性皮炎病灶性皮肤(AL)和HC之间共鉴定出27个DEPRG。富集分析显示这些DEPRG主要富集在炎症反应和角质形成细胞分化中。在通过蛋白质-蛋白质相互作用网络鉴定的10个hub基因中，只有GSDMD与上皮紧密连接核心基因的表达呈统计学负相关。此外，GSDMD在AD病变中上调，并通过减少聚丝团蛋白（FLG）的表达来抑制人角质形成细胞的分化。机械上,由Caspase1激活的GSDMD通过HDAC1降低FLG表达。HDAC1通过减少FLG启动子处的组蛋白乙酰化来降低FLG表达。此外,GSDMD阻断了钾通道四聚化域6（KCTD6）与HDAC1的相互作用，以抑制HDAC1的降解。
■这项研究表明，GSDMD在AD病变中上调，并且GSDMD通过表观遗传修饰调节角质形成细胞，这可能为AD提供潜在的治疗靶点。
■来自基因表达综合(GEO)的AD数据集用于鉴定不同表达的焦亡相关基因(DEPRG)。鉴定Hub基因并进行富集分析以选择上皮发育相关基因。通过免疫组织化学（IHC）检测AD患者的病变以验证hub基因。人角质形成细胞系,gasderminD(GSDMD)过表达,Caspase1siRNA,组蛋白去乙酰化酶1(HDAC1)siRNA,和HDAC1过表达载体用于功能获得和丧失实验。通过qPCR确定角质化蛋白的调节，蛋白质印迹(WB),免疫荧光（IF），双荧光素酶报告分析，免疫共沉淀（Co-IP），和染色质免疫沉淀(ChIP)。
■在特应性皮炎非病灶性皮肤(ANL)和健康对照(HC)或特应性皮炎病灶性皮肤(AL)和HC之间共鉴定出27个DEPRG。富集分析显示这些DEPRG主要富集在炎症反应和角质形成细胞分化中。在通过蛋白质-蛋白质相互作用网络鉴定的10个hub基因中，只有GSDMD与上皮紧密连接核心基因的表达呈统计学负相关。此外，GSDMD在AD病变中上调，并通过减少聚丝团蛋白（FLG）的表达来抑制人角质形成细胞的分化。机械上,由Caspase1激活的GSDMD通过HDAC1降低FLG表达。HDAC1通过减少FLG启动子处的组蛋白乙酰化来降低FLG表达。此外,GSDMD阻断了钾通道四聚化域6（KCTD6）与HDAC1的相互作用，以抑制HDAC1的降解。
■这项研究表明，GSDMD在AD病变中上调，并且GSDMD通过表观遗传修饰调节角质形成细胞，这可能为AD提供潜在的治疗靶点。
