GSDMD suppresses keratinocyte differentiation by inhibiting FLG expression and attenuating KCTD6-mediated HDAC1 degradation in atopic dermatitis

Author:

Zhong Yi1,Huang Taoyuan2,Li Xiaoli1,Luo Peiyi1,Zhang Bingjun3

Affiliation:

1. Department of Dermatology, Guangzhou Women and Children’s Medical Center, Guangzhou, China

2. Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, China

3. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

Abstract

Background 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. Methods 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). Results 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. Conclusion 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.

Funder

The Doctoral Scientific Research Startup Fund of Guangzhou Women and Children’s Medical Center

Basic Research Joint Project of Guangzhou Technology Bureau and Hospital

Publisher

PeerJ

Reference36 articles.

1. FRA1: c-JUN: HDAC1 complex down-regulates filaggrin expression upon TNFalpha and IFNgamma stimulation in keratinocytes;Ahn;Proceedings of the National Academy of Sciences of the United States of America,2022

2. QuPath: open source software for digital pathology image analysis;Bankhead;Scientific Reports,2017

3. NCBI GEO: archive for functional genomics data sets—update;Barrett;Nucleic Acids Research,2013

4. Gasdermin D in pyroptosis;Burdette;Acta Pharmaceutica Sinica B,2021

5. The gene expression omnibus database;Clough;Methods in Molecular Biology,2016

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