PIASy as a negative regulator of Th17 pathway in psoriasis

说明（由申请人提供）：免疫是宿主防御外来病原体入侵所必需的。Th17通路被上皮细胞、T细胞、树突状细胞之间的动态相互作用激活。在正常生理条件下，Th17通路受到严密控制，可预防慢性炎症。然而，组成型Th17激活是许多慢性炎症性疾病（包括类风湿关节炎和牛皮癣）的常见病理特征。到目前为止，Th17炎症性疾病中组成型Th17激活的分子基础在很大程度上仍然未知。在这项研究中，我们提供了实验证据，表明PIASy的失活有助于组成型Th17的激活。piasy缺陷小鼠出现牛皮癣样表型，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对TNFα和IL-17A的反应中IL-23的强烈表达。这是首次证明人类银屑病角质形成细胞在TNFα和IL-17A的作用下产生强大的IL-23。由于IL-23对Th17的激活至关重要，因此角化细胞中Th17细胞因子诱导IL-23通过银屑病角化细胞过量分泌IL-23和Th17 T细胞过量分泌il - 17/TNFα细胞因子，为形成Th17激活的正调控环提供了分子基础。生物化学方面，我们发现NFκB和STAT3是PIASy负调控的靶点。由于NFκB和STAT3是银屑病炎症回路的主要贡献者，我假设PIASy的失活有助于银屑病中Th17的持续激活。1)建立PIASy失活的临床相关性及其与IL-23表达和活化的相关性

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.