Inflammatory Mediators Suppress FGFR2 Expression in Human Keratinocytes to Promote Inflammation.

IF 3.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular and Cellular Biology Pub Date : 2024-01-01 Epub Date: 2024-09-28 DOI:10.1080/10985549.2024.2399766
Luca Ferrarese, Michael Koch, Artemis Baumann, Liliana Bento-Lopes, Daria Wüst, Ivan Berest, Manfred Kopf, Sabine Werner
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Abstract

Fibroblast growth factors (FGFs) are key orchestrators of development, tissue homeostasis and repair. FGF receptor (FGFR) deficiency in mouse keratinocytes causes an inflammatory skin phenotype with similarities to atopic dermatitis, but the human relevance is unclear. Therefore, we generated human keratinocytes with a CRISPR/Cas9-induced knockout of FGFR2. Loss of this receptor promoted the expression of interferon-stimulated genes and pro-inflammatory cytokines under homeostatic conditions and in particular in response to different inflammatory mediators. Expression of FGFR2 itself was strongly downregulated in cultured human keratinocytes exposed to various pro-inflammatory stimuli. This is relevant in vivo, because bioinformatics analysis of bulk and single-cell RNA-seq data showed strongly reduced expression of FGFR2 in lesional skin of atopic dermatitis patients, which likely aggravates the inflammatory phenotype. These results reveal a key function of FGFR2 in human keratinocytes in the suppression of inflammation and suggest a role of FGFR2 downregulation in the pathogenesis of atopic dermatitis and possibly other inflammatory diseases.

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炎症介质抑制人角质形成细胞中表皮生长因子受体 2 的表达,从而促进炎症。
成纤维细胞生长因子(FGF)是发育、组织稳态和修复的关键协调因子。小鼠角质形成细胞中的成纤维细胞生长因子受体(FGFR)缺乏会导致皮肤炎症表型,与特应性皮炎相似,但与人类的相关性尚不清楚。因此,我们用 CRISPR/Cas9 诱导的 FGFR2 基因敲除技术生成了人类角质形成细胞。该受体的缺失促进了干扰素刺激基因和促炎细胞因子在平衡状态下的表达,尤其是在对不同炎症介质的反应中。在受到各种促炎刺激的培养人角质形成细胞中,表皮生长因子受体 2 本身的表达强烈下调。这与体内情况有关,因为对大量和单细胞 RNA-seq 数据进行的生物信息学分析表明,在特应性皮炎患者的病变皮肤中,FGFR2 的表达强烈下降,这可能会加重炎症表型。这些结果揭示了 FGFR2 在人类角质形成细胞中抑制炎症的关键功能,并表明 FGFR2 的下调在特应性皮炎以及其他可能的炎症性疾病的发病机制中发挥作用。
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来源期刊
Molecular and Cellular Biology
Molecular and Cellular Biology 生物-生化与分子生物学
CiteScore
9.80
自引率
1.90%
发文量
120
审稿时长
1 months
期刊介绍: Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.
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