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NLRP1 inflammasome activation in skin equivalents reveals mechanistic insights into the roles of keratinocytes in psoriasis

ABSTRACT: Psoriasis is a common inflammatory disease that affects mainly the skin. The pro-inflammatory cytokines interleukin(IL)-1β and IL-36γ are involved in its pathogenesis. However, the molecular and cellular mechanisms underlying the regulation of these pathways in psoriasis are incompletely understood. IL-1β activity is produced downstream of a group of protein complexes termed inflammasomes, which are primarily expressed by immune cells. To address the function of the NLRP1 inflammasome in epidermal keratinocytes, we activated NLRP1 pharmacologically in human skin equivalents (SEs), an organotypic three-dimensional skin model. In the epidermis of these SEs, IL-1β secretion induced a histological phenotype that resembles psoriasis and is associated with a characteristic pro-inflammatory gene expression signature, including the induction of IL-36γ expression and secretion. Whereas expression of IL-36γ is induced by IL-1β, IL-36γ secretion occurs downstream of NLRP1 activation through gasdermin D pores. Most importantly, we detected inflammasome activation in suprabasal keratinocytes in lesional psoriasis. Release of endogenous double stranded (ds) RNA to the cytoplasm is associated with cellular perturbations in several inflammatory conditions, including psoriasis. In keratinocytes in monoculture, we identified short self-derived dsRNA as a novel activator of the NLRP1 inflammasome. These data suggest a critical role of keratinocytes in the pathogenesis of psoriasis through activation of the NLRP1 inflammasome. Furthermore, NLRP1-activated SEs represent a novel in vitro model for this condition, based on human primary skin cells. Most importantly, pharmacological targeting and inhibition of NLRP1 appears as a novel treatment option for psoriasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282206 | GEO | 2025/09/23

REPOSITORIES: GEO

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Project description:Transcriptional profiling of Homo sapiens inflammatory skin diseases (whole skin biospies): Psoriasis (Pso), vs Atopic Dermatitis (AD) vs Lichen planus (Li), vs Contact Eczema (KE), vs Healthy control (KO) In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/TNFα-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, due to its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation. In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/TNFα-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, due to its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.

Project description:The inflammasome sensor NLRP1 is mainly expressed by epithelial cells including keratinocytes of human skin. Germline gain-of-function mutations in NLRP1 cause inflammatory skin syndromes and predispose patients to the development of cutaneous squamous cell carcinomas (cSCCs), a major type of skin cancer originating from keratinocytes. However, expression of NLRP1 is strongly reduced in cSCCs suggesting a complex role of the NLRP1 inflammasome in the development of this type of skin cancer. Suppression of NLRP1 expression in SCC cells is partially caused by an increase in p62 (SQSTM1), a cargo receptor for autophagy-dependent protein degradation. p62 is upregulated in numerous types of cancer and plays key roles in tumor development by activating different pathways. Here, we characterized the molecular mechanisms underlying suppression of NLRP1 expression by p62 in cSCCs. In SCC cells, NLRP1 activation is rescued by a knockdown or knockout of p62 mRNA and, consequently, protein expression, rather than by a knockout of p62 protein expression only. As these experiments suggest a regulation of NLRP1 by the p62 mRNA, we characterized p62 mRNA-regulated gene expression in SCC cells through RNA sequencing. In addition to mRNAs, we identified several differentially regulated microRNAs (miRs), including miR-34a-5p. These short non-coding RNAs regulate the stability or translation of mRNAs in a dynamic manner and a single miR can target multiple mRNAs. miR-34a-5p is an established tumor suppressor in different types of cancer and its expression is also downregulated in cSCCs. Although miR-34a-5p seems to bind neither p62 nor NLRP1 mRNA directly, it increases NLRP1 expression, most likely through a complex mechanism at the RNA level. In summary, our findings revealed a novel pathway regulating suppression of the inflammasome sensor NLRP1 in SCC cells by p62, which occurs at the mRNA level and is mediated by miRs, including the tumor suppressive miR-34a-5p. p62 mRNA, but not protein, regulates expression of other mRNAs and miRNAs. Differential expression analysis of RNA-seq data from SCC12 cells with a protein (p62.1) or mRNA (p62.2K) knockout, and control cells were performed. CRISPR/Cas9 knockout (p62.1 - protein only) or CRISPR/dCas9-KRAB knockout (p62.2K - mRNA and protein) of p62 in SCC12 cells

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NLRP1 inflammasome activation in skin equivalents reveals mechanistic insights into the roles of keratinocytes in psoriasis

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