GSDME deficiency leads to the aggravation of UVB-induced skin inflammation through enhancing recruitment and activation of neutrophils

Abstract

Gasdermin E (GSDME)-mediated pyroptosis is induced in keratinocytes of UVB-challenged skin. The role of GSDME in UVB-caused skin damage remains unknown. To explore the role of GSDME in UVB-induced skin inflammation. We compared differences in skin appearance, histological features, keratinocyte death modalities, infiltration of immune cells, and levels of some inflammatory cytokines between Gsdme−/− mice and wild type (WT) mice after UVB exposure. We explored whether keratinocytes contribute to GSDME deficiency-caused aggravation of UVB-induced skin inflammation in GSDME knockdown keratinocyte cultured in vitro and keratinocyte-specific Gsdme conditional knockout mice. We used anti-Ly6G antibody to deplete neutrophils and explore their role in UVB-caused skin damage. Skin damage and neutrophils infiltration were aggravated in UVB-challenged Gsdme−/− mice, compared with UVB-challenged WT mice. Apoptosis and necroptosis, which were initiated together with GSDME-mediated pyroptosis in UVB-challenged WT mice, were not enhanced in UVB-challenged Gsdme−/− mice. Neutrophils activation indicators and its recruiting cytokines were increased in skin tissue of UVB-challenged Gsdme−/− mice. However, GSDME knockdown did not lead to the further increase of mRNA and secretion of TNF-α and IL-6 in UVB-challenged keratinocytes. Skin damage was not aggravated in UVB-challenged Gsdme cKO mice. Neutrophils depletion alleviated UVB-caused skin damage in WT mice and Gsdme−/− mice, and eliminated its aggravation in Gsdme−/− mice. This study demonstrates that GSDME plays a restrictive role in UVB-induced skin damage through inhibiting excessive recruitment and activation of neutrophils in the immune microenvironment in UVB-caused skin inflammation. However, keratinocytes might not contribute to this restrictive function.

Gasdermin E (GSDME)—A New Potential Marker of Psoriasis and Its Metabolic Complications: The First Combined Study on Human Serum, Urine and Tissue

“…Similar observations were first made by Chen et al [22]. The same team extended their research and found later that after UVB radiation exposure, different cell deaths in the mice's epidermis occurred at the same time, namely GSDME-mediated pyroptosis, apoptosis and necroptosis [23], which confirms the diverse nature of GSDME we mentioned in the introduction. GSDME has also been reported to play a role as a mediator in the sustained chronic inflammatory skin condition in zebra fish [24].…”

Comprehensive bioinformatics analysis to identify a novel Ferroptosis-related gene and its ceRNA regulatory network and candidate Therapeutic Agents in UVB-irradiated human skin

“…And GSDME de ciency leads to the aggravation of UVB-induced skin in ammation through enhancing recruitment and activation of neutrophils. We also analyzed the correlations between IL6 expression and immune cell in ltration ratio and found that important molecular markers for UVB-treated are related to the ratio of Neutrophils (Chen et al, 2022). Of course, we cannot rule out the error of the CIBERSORT algorithm in calculating, but our work promotes the study of the immune response in skin after UVB irradiation.…”

“…Microarray technology has been widely used to investigate a variety of biological systems, thanks to the rapid development of computer science, and technology is being used in an increasing number of studies to investigate immunology and the pathophysiology of in ammatory diseases (Karasinska et al, 2020; Villaseñor-Park & Ortega-Loayza, 2013; Zhang et al, 2022).To avoid the false-positive rates of independent microarray analysis data, we combined two microarray data sets from Gene Expression Omnibus (GEO) and batchnormalized it for analysis to identify key genes between the control group and the UVB-treated group. the examination of gene expression pro les is considered an essential process to explore the functional elements of the genome and understand the associations between hazardous factors and induced molecular mechanisms.…”

A novel risk score model based on pyroptosis-related genes for predicting survival and immunogenic landscape in hepatocellular carcinoma

“…Therefore, GSDME-modulated pyroptosis may play a vital role in chemotherapy-induced nephrotoxicity. Moreover, loss of GSDME also aggravated skin damage in UVB-treated mice by promoting the infiltration and activation of neutrophils [ 61 ]. Previous studies have identified NOD1 as a key player in host-microbial defense and multiple inflammatory diseases.…”