STAT2 Signaling in the Pathogenesis of Psoriasis

银屑病发病机制中的 STAT2 信号转导

基本信息

批准号：
10303865
负责人：
ANA M GAMERO
金额：
$ 20.92万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303865
关键词：
Abnormal Keratinocyte Affect Agonist Anabolism Animal Model Attenuated Binding Sites Biological Biopsy Cell Maturation Cells Chronic Colon Carcinoma Complex Cues Data Dendritic Cells Dermal Disease Epithelial Cells Epithelium Etiology Feedback Functional disorder Gene Expression Profile Generations Genes Genetic Transcription Homeostasis Human IFNAR1 gene IL17 gene Imiquimod Immune Immune system Immunologics Impairment Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type I Interferons Interleukin-1 beta Interleukin-17 Interleukin-6 Lesion Link Lipids Mediating Mediator of activation protein Modeling Molecular Monitor Mus Natural regeneration Nature Pathogenesis Patients Population Predisposition Process Psoriasis Quality of life Role STAT1 gene STAT2 gene Severities Signal Pathway Signal Transduction Signaling Protein Skin Stat2 protein Susceptibility Gene T-Lymphocyte TLR7 gene Testing Ubiquitination autoinflammatory base cell type chronic inflammatory skin cytokine differential expression epithelium regeneration genome wide association study human disease immune activation in vivo inflammatory marker interleukin-22 interleukin-23 keratinocyte keratinocyte differentiation lipid biosynthesis lipid metabolism lipidome lipidomics mouse model novel preservation prevent promoter protein expression skin disorder skin lesion stemness transcription factor transcriptome transcriptome sequencing type I interferon receptor

项目摘要

Summary Psoriasis is an incurable multifactorial chronic inflammatory skin disorder of unknown etiology that is characterized by dermal infiltration of immune cells accompanied by hyperproliferation and abnormal differentiation of keratinocytes. Along with the IL-23/IL-17/IL-22/IL-36 inflammatory signaling axis, the type I Interferon (IFN-I) signaling pathway is another recognized driver of psoriasis. Assembly of the transcriptional ISGF3 complex consisting of STAT1/STAT2/IRF9 mediates the expression of IFN-I target genes. Studies in mice lacking type I IFN receptor (IFNAR1) or defective in IFNAR1 ubiquitination show IFN-I as a damaging cytokine in psoriasis. Aside from being pro-inflammatory, IFN-I can reprogram lipid biosynthesis and alterations in lipid metabolism is an important factor in the pathogenesis of psoriasis; which has also been described as an immunometabolic disease. STAT2 is a key signaling mediator of IFN-I signaling and emerging evidence links STAT2 to psoriasis. Genome-wide association studies have identified STAT2 as a psoriasis susceptibility gene. Psoriatic skin lesions from patients display an IFN-I transcriptional signature and, notably, activation of STAT2. For this proposal, we present preliminary data depicting the pro-inflammatory nature of STAT2 in psoriasis. Imiquimod (TLR7/8 agonist)-induced psoriasis-like skin inflammation in Stat2 deficient mice was drastically attenuated. Conventional dendritic cells (cDCs) are active players in psoriatic inflammation. We show that deletion of Stat2 only in cDCs impaired TLR7/8 mediated maturation in vivo. Furthermore, we found Stat2 to be critical for the psoriasis-associated cytokine IL-36 to enhance IFN-I signaling. In an unrelated study on colon cancer, we show that Stat2 mediates the expression of pro-inflammatory cytokines IL1-β, IL-6, IL-17 and IL-22 and alters lipid metabolism. These latter findings lend support to the potential involvement of STAT2 in promoting inflammation and lipid dysregulation in the skin. Based on these observations, we will test the hypothesis that aberrant STAT2 signaling contributes to the pathogenesis of psoriasis by disrupting immune/epithelial homeostasis and altering lipid metabolite composition, thereby promoting an inflammatory amplification cycle that leads to severe skin inflammation. For this proposal, we have developed two specific aims in which we will employ conventional Stat2KO mice and our recently generated conditional Stat2KO mouse. Aim 1 will determine whether Stat2 signaling in cDCs drives the generation and reactivation of a Th17/IlL22 axis to obstruct normal keratinocyte maturation. Aim 2 will determine whether Stat2 signaling in keratinocytes obstructs epidermal regeneration; preserves cell stemness and promotes changes in lipid composition of the skin and incites an inflammatory positive feedback loop causing aberrant immune cell activation. Significance: Successful completion of this project will bridge a significant gap in our current understanding of STAT2 in the pathogenesis of psoriasis. We anticipate identifying novel inflammatory markers for monitoring psoriasis, as well.

概括银屑病是一种病因不明的无法治愈的多因素慢性炎症性皮肤病，其特征是免疫细胞浸润真皮，伴有角质形成细胞过度增殖和异常分化以及 IL-23/IL-17/IL-22/IL-36 炎症信号传导。轴，I 型干扰素 (IFN-I) 信号通路是银屑病的另一个公认驱动因素，其由转录 ISGF3 复合物组成。 STAT1/STAT2/IRF9 介导 IFN-I 靶基因的表达。对缺乏 I 型 IFN 受体 (IFNAR1) 或 IFNAR1 泛素化缺陷的小鼠进行的研究表明，IFN-I 除了具有促炎作用外，还是银屑病中的一种破坏性细胞因子。 -我可以重新编程脂质生物合成和脂质代谢的改变是牛皮癣发病机制的一个重要因素，这也被描述为免疫代谢； STAT2 是 IFN-I 信号传导的关键信号介导物，并且新的证据表明 STAT2 与银屑病有关。，STAT2 的激活对于该提议，我们提供了描述 STAT2 在银屑病中的促炎性质的初步数据。我们发现，Stat2 缺陷小鼠中 Stat2 诱导的银屑病样皮肤炎症在银屑病炎症中发挥着积极作用。 Stat2 对于银屑病相关细胞因子 IL-36 增强 IFN-I 信号传导至关重要。在一项与结肠癌无关的研究中，我们发现这一点。 Stat2 介导促炎细胞因子 IL1-β、IL-6、IL-17 和 IL-22 的表达，并改变脂质代谢，这些发现支持了 STAT2 可能参与促进皮肤炎症和脂质失调。基于这些观察结果，我们将检验以下假设：异常的 STAT2 信号传导通过破坏免疫/上皮稳态和改变脂质代谢物组成，从而促进炎症，从而促进银屑病的发病机制。对于导致严重皮肤炎症的扩增循环，我们制定了两个具体目标，其中我们将使用传统的 Stat2KO 小鼠和我们最近生成的条件 Stat2KO 小鼠，目标 1 将确定 Stat2 信号传导是否驱动 cDC 的生成和重新激活。 Th17/IlL22 轴阻碍正常角质形成细胞成熟；目标 2 将确定角质形成细胞中的 Stat2 信号传导是否阻碍表皮再生；促进皮肤脂质成分的变化并引发炎症正反馈循环，导致异常的免疫细胞激活。意义：该项目的成功完成将弥补我们目前对银屑病发病机制中 STAT2 的理解的重大差距。以及监测牛皮癣的标记物。