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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：
10418798
负责人：
ANA M GAMERO
金额：
$ 17.26万
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/10418798
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.

总结银屑病是一种病因不明的无法治愈的多因素慢性炎性皮肤病，其特征在于免疫细胞的真皮浸润，伴有角质形成细胞的过度增殖和异常分化。沿着IL-23/IL-17/IL-22/IL-36炎症信号传导轴，I型干扰素（IFN-I）信号传导途径是银屑病的另一种公认的驱动因素。由STAT 1/STAT 2/IRF 9组成的转录ISGF 3复合物的组装介导IFN-1靶基因的表达。在缺乏I型IFN受体（IFNAR 1）或IFNAR 1泛素化缺陷的小鼠中的研究表明，IFN-I是银屑病中的破坏性细胞因子。除了是促炎性的，IFN-I可以重编程脂质生物合成，并且脂质代谢的改变是银屑病发病机制中的重要因素;银屑病也被描述为免疫代谢疾病。STAT 2是IFN-I信号传导的关键信号传导介质，并且新出现的证据将STAT 2与银屑病联系起来。全基因组关联研究已将STAT 2确定为银屑病易感基因。患者的银屑病皮肤病变显示IFN-I转录特征，特别是STAT 2的激活。对于这一建议，我们提出了初步的数据描绘的促炎性的STAT 2在银屑病。咪喹莫特（TLR 7/8激动剂）诱导的Stat 2缺陷小鼠中的银屑病样皮肤炎症显著减弱。传统的树突状细胞（cDC）是银屑病炎症的活跃参与者。我们表明，Stat 2的缺失，只有在cDCs损害TLR 7/8介导的体内成熟。此外，我们发现Stat 2对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Stat 2介导促炎细胞因子IL-1-β、IL-6、IL-17和IL-22的表达，并改变脂质代谢。后一项发现支持STAT 2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STAT 2信号传导通过破坏免疫/上皮稳态和改变脂质代谢物组成，从而促进导致严重皮肤炎症的炎症放大循环，从而促进银屑病的发病机制。对于这个提议，我们已经开发了两个特定的目标，其中我们将使用传统的Stat 2KO小鼠和我们最近生成的条件Stat 2KO小鼠。目的1将确定cDC中的Stat 2信号传导是否驱动Th 17/IL 22轴的产生和再活化以阻碍正常角质形成细胞成熟。目的2将确定角质形成细胞中的Stat 2信号传导是否阻碍表皮再生;保持细胞干性并促进皮肤脂质组成的变化，并引发引起异常免疫细胞活化的炎症正反馈回路。重要性：该项目的成功完成将弥补我们目前对STAT 2在银屑病发病机制中的理解的重大空白。我们也期待发现新的炎症标志物来监测银屑病。