PIASy as a negative regulator of Th17 pathway in psoriasis

PIASy 作为银屑病 Th17 通路的负调节因子

• 批准号: 9089602
• 负责人: YUANGANG LIU
• 金额: $ 7.7万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089602
• 关键词: Affect; Cell Differentiation process; Chronic; Combined Modality Therapy; Defect; Dendritic Cells; Disease; Enzymes; Epithelial Cells; Feedback; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Health; Host Defense; Human; IL17 gene; Imiquimod; Immunity; Infection; Inflammation; Inflammation Process; Inflammatory; Interleukin-17; Kinetics; Knockout Mice; Leukocytes; Measures; Mediating; Molecular; Mus; NF-kappa B; Pathway interactions; Patients; Phenotype; Phosphorylation; Physiological; Population; Prevention therapy; Production; Psoriasis; Regulation; Rheumatoid Arthritis; Role; STAT3 gene; Skin; Skin graft; Subfamily lentivirinae; T cell differentiation; T-Lymphocyte; TNF gene; Testing; Time; base; cell type; chronic inflammatory skin; clinically relevant; cytokine; design; interleukin-23; keratinocyte; novel strategies; outcome forecast; overexpression; pathogen; prevent; response; skin disorder; skin organogenesis; small hairpin RNA; treatment response

DESCRIPTION (provided by applicant): The immunity is essential for host defense against the invasion of foreign pathogens. The Th17 pathway is activated by dynamic interplays among epithelial cells, T cells, dendritic cells. Under normal physiological conditions, Th17 pathway is tightly controlled to prevent chronic inflammation. However, constitutive Th17 activation is a common pathological feature in many chronic inflammatory diseases including rheumatoid arthritis and psoriasis. So far the molecular basis of constitutive Th17 activation in Th17 inflammatory diseases remains largely unknown. In this study, we have provided experimental evidence to suggest that the inactivation of PIASy contributes to constitutive Th17 activation. PIASy-deficient mice developed psoriasis-like phenotypes and showed increased Th17 cytokine expression in response to topical imiquimod treatment. More importantly, PIASy deficiency resulted in robust expression of IL-23 from keratinocytes in response to the treatment of TNFα and IL-17A. This is the first time to demonstrate that human psoriatic keratinocytes produce robust IL-23 in response to TNFα and IL-17A. As IL-23 is essential for Th17 activation, IL-23 induction by Th17 cytokines in keratinocytes provides a molecular basis for forming a positive regulatory loop of Th17 activation through IL-23 overproduction from psoriatic keratinocytes and IL17/TNFα cytokine overproduction from Th17 T cells. Biochemically, we have identified NFκB and STAT3 as the targets negatively regulated by PIASy. As NFκB and STAT3 are the major contributors in the inflammation circuitry of psoriasis, I hypothesize that inactivation of PIASy contributes to sustained Th17 activation in psoriasis. This hypothesis will be tested by 1) Establish the clinical relevance of PIASy inactivation and its correlation with IL-23 expression and the activation of NF-kB and STAT3 in human psoriasis~ 2) Defining the functional role of PIASy in IL23 expression from keratinocytes~ 3) Defining the functional role of PIASy in Th17 T cells differentiation and IL17 expression from Th17 T cells. The analysis of the PIASy molecular pathway in Th17 regulation will not only enable us to understand the molecular basis of aberrant inflammation in psoriasis, but also provide novel strategies for psoriasis prognosis, prevention and therapy.

描述(申请人提供)：免疫力是宿主抵御外来病原体入侵所必需的。Th17通路通过上皮细胞、T细胞、树突状细胞之间的动态相互作用而被激活。在正常生理条件下，Th17通路受到严格控制，以防止慢性炎症。然而，结构性Th17激活是许多慢性炎症性疾病的共同病理特征，包括类风湿性关节炎和银屑病。到目前为止，Th17炎症性疾病中结构性Th17激活的分子基础仍不清楚。在这项研究中，我们提供了实验证据，表明PIASy的失活有助于结构性Th17的激活。PIASY缺陷小鼠出现牛皮癣样表型，并表现出局部咪喹莫特治疗后Th17细胞因子表达增加。更重要的是，PIASY缺陷导致角质形成细胞在肿瘤坏死因子α和IL-17A治疗后强烈表达IL-23。这是第一次证明银屑病角质形成细胞在肿瘤坏死因子α和IL-17A的作用下产生强大的IL-23。由于IL-23是Th1 7激活所必需的，因此在角质形成细胞中，Th1 7细胞因子诱导的IL-2 3可通过银屑病角质形成细胞过度产生IL-23和Th1 7 T细胞过度产生IL 17/肿瘤坏死因子α，形成Th1 7激活的正向调控环。在生化方面，我们已将NFκB和STAT3确定为PIASy负调控的靶点。由于核因子κB和STAT3是银屑病炎症回路中的主要贡献者，我推测PIASY的失活有助于银屑病中Th17的持续激活。这一假说将通过1)建立PIASy失活的临床相关性及其与IL-23表达和PIASy激活的相关性来验证 2)明确PIASy在角质形成细胞IL23表达中的功能作用；3)确定PIASy在Th17 T细胞分化和Th17 T细胞表达IL17中的功能作用。分析PIASy在Th17调节中的分子途径，不仅有助于我们了解银屑病异常炎症的分子基础，而且为银屑病的预后、预防和治疗提供新的策略。