IL-17C mediated mechanisms of inflammation

IL-17C 介导的炎症机制

• 批准号: 8445590
• 负责人: Nicole Leanne Ward
• 金额: $ 36.37万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445590
• 关键词: Acanthosis; Address; Adverse reactions; Affect; American; Animals; Antibodies; Area; Binding; Biological; Biological Assay; Blocking Antibodies; CCL20 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Chronic; Clinical; Coculture Techniques; Coupled; Cutaneous; Data; Dermal; Dermatitis; Development; Disease; Disease remission; Doxycycline; Endothelial Cells; Endothelium; Epidermis; Epithelial; Epithelial Cells; Event; Exhibits; Family; Family member; Feedback; Future; Genes; Genetic; Genetically Engineered Mouse; Human; Hyperplasia; IL17C gene; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Interleukin-17; Intervention; Kinetics; Knock-out; Leukocytes; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Paper; Pathogenesis; Patients; Pattern; Phenotype; Population; Positioning Attribute; Prevalence; Production; Psoriasis; Recombinants; Reporting; Resolution; Serum; Signal Pathway; Signal Transduction; Signs and Symptoms; Skin; T-Lymphocyte; TNF gene; Technology; Testing; Therapeutic; Tissues; Translating; Tumor Necrosis Factor Receptor; Work; angiogenesis; base; cellular targeting; cost; cytokine; gene induction; gene repression; inhibitor/antagonist; innovation; insight; interleukin-17C; interleukin-22; keratinocyte; member; mouse model; novel; novel therapeutics; overexpression; public health relevance; response; skin disorder; socioeconomics; therapeutic development

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.

描述（由申请人提供）：IL-17C是IL-17细胞因子家族中功能独特的新型成员，通过IL-17RE和IL-17RA发挥作用，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 (KC)、内皮细胞 (EC) 和白细胞并对其产生影响。我们的初步数据表明，IL-17C 刺激后，CD4+ T 细胞衍生的 IL-17A 和 IL-22（Th17 和 Th22）以及 EC 衍生的 TNFa 增加。有趣的是，用IL-17C和TNF刺激的KC产生与IL-17A/TNF刺激相似的协同炎症基因反应模式（但幅度更高），并且这些基因反应模式随着IL-17A的添加而进一步增强，表明内皮、表皮和Th17/22细胞之间存在正向促炎反馈回路。在接受 TNFa 抑制剂治疗的银屑病患者中，皮肤 IL-17C 表达在皮肤改善之前迅速下降（72 小时内），并且 IL-17A 和 IL-22 的血清水平降低，表明 IL-17C 可能作为放大 Th17/22/TNFa 介导的炎症信号的新机制，该信号对于银屑病发病机制至关重要。为了进一步探讨 IL-17C 在介导银屑病炎症中的重要性，我们对小鼠进行了基因改造，使其在 KC 中过度表达 IL-17C。小鼠皮肤发育出界限清楚的未受累组织区域，其特征是在没有表皮增生的情况下血管生成增加和适度的白细胞浸润，以及受累皮肤的邻近区域表现出强烈的表皮增生、白细胞浸润增加以及 TNFa、IL-17A 和 IL-22 增加；表明 IL-17C 与其他促炎信号结合时会导致银屑病样皮肤皮炎的发生。总而言之，这些观察结果表明 IL-17C 是 IL-17 家族的快速反应成员，它协同激活 KC、内皮细胞和 Th17/22 细胞之间的促炎反馈环路，并且可能在银屑病中至关重要。 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，结合体外细胞共培养、SiRNA、细胞信号传导和生物测定方法来测试以下假设：IL-17C 结合靶细胞上的 IL-17RE/A 上调 TNF¿ (EC) 和 IL-17/IL-22 (Th17/22) 与 IL-17C 协同诱导 KC 激活和表皮增生。我们打算将 IL-17C 确定为引发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 IL-17C 以及用于指导 KC、EC 和 Th17/22 细胞反应的潜在机制，这些反应转化为银屑病中持续的炎症和棘皮症。这项工作将为未来探索靶向 IL-17C 或 IL-17RE 治疗银屑病的治疗开发潜力的工作提供基础和理由。