IL-17C mediated mechanisms of inflammation

描述（由申请人提供）：IL- 17c是IL-17细胞因子家族中一种功能独特的新成员，通过IL- 17RE和IL- 17ra促进上皮细胞的先天防御并调节Th17细胞分化。在人银屑病组织中，IL-17C在病变皮肤中高表达，定位于角质形成细胞（KCs）、内皮细胞（ECs）和白细胞并对其产生影响。我们的初步数据显示，在IL-17C刺激后，CD4+ T细胞来源的IL-17A和IL-22 （Th17和Th22）以及ec来源的TNFa增加。有趣的是，受IL-17C和TNF -刺激的KCs产生与IL-17A/TNF -引发的相似的协同炎症基因反应模式（但强度更高），并且这些基因反应模式随着IL-17A的加入而进一步增强，表明内皮、表皮和Th17/22细胞之间存在积极的促炎反馈回路。在接受TNFa抑制剂治疗的银屑病患者中，皮肤IL-17C表达在皮肤改善前（72小时内）迅速下降，血清IL-17A和IL-22水平下降，这表明IL-17C可能是放大Th17/22/TNFa介导的炎症信号的新机制，对银屑病的发病至关重要。为了进一步探索IL-17C在介导银屑病炎症中的重要性，我们通过基因工程使小鼠在KCs中过表达IL-17C。小鼠皮肤的未受累组织区域界限清晰，其特征是在没有表皮增生的情况下，血管生成增加，白细胞浸润适度，受累皮肤的邻近区域表现出强烈的表皮增生，白细胞浸润增加，TNFa、IL-17A和IL-22增加；提示IL-17C与其他促炎信号结合可导致银屑病样皮肤皮炎的发生。综上所述，这些观察结果表明，IL-17C是IL-17家族中反应迅速的成员，它协同激活KCs、内皮和Th17/22细胞之间的促炎反馈回路，可能在银屑病中起关键作用。我们将使用这种创新的新小鼠模型、基因敲除方法、cre-lox技术和抗体靶向策略，以及体外细胞共培养、SiRNA、细胞信号传导和生物测定方法来验证IL-17C结合IL-17RE/A在靶细胞上上调TNF - (EC)和IL-17/IL-22 （Th17/22）的假设，这些因子与IL-17C协同作用，诱导KC活化和表皮增生。我们打算确定IL-17C是启动和维持慢性皮肤炎症所需的关键早期上游促炎细胞因子，并确定受影响的关键细胞靶点

DESCRIPTION (provided by applicant): IL-17C is a novel and functionally distinct member of the IL-17 family of cytokines and acts through IL- 17RE and IL-17RA to promote innate defense in epithelial cells and regulate Th17 cell differentiation. In human psoriasis tissue, IL-17C is highly expressed in lesional skin and localizes to and exerts effects upon keratinocytes (KCs), endothelial cell (ECs) and leukocytes. Our preliminary data demonstrates increases in CD4+ T cell-derived IL-17A and IL-22 (Th17 and Th22) and EC-derived TNFa following IL-17C stimulation. Interestingly, KCs stimulated with IL-17C and TNF� produce similar synergistic inflammatory gene response patterns as those elicited by IL-17A/TNF� (but at higher magnitudes) and these gene response patterns are further enhanced with the addition of IL-17A, indicating a positive pro-inflammatory feedback loop between the endothelium, epidermis and Th17/22 cells. In psoriasis patients treated with TNFa inhibitors, cutaneous IL-17C expression decreases rapidly (within 72h) prior to skin improvement and decreases in serum levels of IL-17A and IL-22 suggesting IL-17C may serve as a novel mechanism for amplifying Th17/22/TNFa mediated inflammatory signaling critical for psoriasis pathogenesis. To further explore the importance of IL-17C in mediating psoriasiform inflammation, we genetically engineered mice to overexpress IL-17C in KCs. Murine skin develops well demarcated areas of uninvolved tissue, characterized by increased angiogenesis and modest leukocyte infiltration in the absence of epidermal hyperplasia as well as adjacent areas of involved skin that exhibit robust epidermal hyperplasia, increased leukocyte infiltration and increases in TNFa, IL-17A, and IL-22; suggesting that IL-17C, when coupled with other pro-inflammatory signals, leads to the development of psoriasiform skin dermatitis. Taken together, these observations suggest that IL-17C is a rapidly responsive member of the IL-17 family and that it synergistically activates a proinflammatory feedback loop between KCs, the endothelium and Th17/22 cells and may be critical in psoriasis. We will use this innovative new mouse model, genetic knockout approaches, cre-lox technologies and antibody targeting strategies coupled with in vitro cell co-culture, SiRNA, cell signaling and bioassay approaches to test the hypothesis that: IL-17C binding IL-17RE/A on target cells up regulates TNF� (EC) and IL-17/IL-22 (Th17/22) that combine synergistically with IL-17C to induce KC activation and epidermal hyperplasia. We intend to identify IL-17C as a critical early upstream proinflammatory cytokine required for initiating and sustaining chronic skin inflammation, and identify the key cellular targets affected by IL-17C as well as the potential mechanism(s) used to direct KC, EC and Th17/22 cell responses that translate to sustaining inflammation and acanthosis in psoriasis. This work will provide the basis and justification for future work exploring the potential of targeting IL-17C or IL-17RE for therapeutic development for the treatment of psoriasis.