IL-17C mediated mechanisms of inflammation

IL-17C 介导的炎症机制

基本信息

批准号：
9039538
负责人：
Nicole Leanne Ward
金额：
$ 40.02万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9039538
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 Cre-LoxP 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 Health Human Hyperplasia IL17C gene In Vitro Infection Infiltration Inflammation Inflammatory Interleukin-17 Intervention Kinetics Knock-out Knockout Mice 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 recombinase-mediated cassette exchange reduce symptoms response skin disorder socioeconomics therapeutic development

项目摘要

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（由适用提供）：IL-17C是IL-17细胞因子家族的新颖且功能上不同的成员，并通过IL-17RE和IL-17RA起作用，以促进上皮细胞中的先天防御，并调节Th17细胞分化。在人牛皮癣组织中，IL-17C在病变的皮肤中高度表达，并定位并对角质形成细胞（KCS），内皮细胞（ECS）和白细胞产生影响。我们的初步数据表明，在IL-17C刺激后，CD4+ T细胞衍生的IL-17A和IL-17A和IL-22（TH17和TH22）以及EC衍生的TNFA的增加。 Interestingly, KCs stimulated with IL-17C and TNF¿ produced similar synergistic inflammatory gene response patterns as those elicited by IL-17A/TNF¿ (but at higher magnitures) and these gene response patterns are further enhanced with the addition of IL-17A, indicating a positive pro-inflammatory feedback loop between the endotherium, epidermis and Th17/22 cells.在用TNFA抑制剂治疗的牛皮癣患者中，皮肤IL-17C表达在改善皮肤之前迅速降低（在72H之内），而IL-17A和IL-22的血清水平降低，IL-22的血清水平表明IL-17C可能是一种新型机制，可作为扩增TH17/22/TNFA介导的繁殖率的新型机制。为了进一步探索IL-17C在介导牛皮癣形象感染中的重要性，我们通常通过KCS中的IL-17C进行过表达IL-17C。鼠类皮肤发展出良好的未参与组织的区域，其特征是血管生成和谦虚的白细胞浸润在没有表皮增生的情况下以及涉及皮肤的邻近区域，可暴露于鲁棒的表皮增生，白细胞浸润和增加TNFA中的白细胞浸润和增加。提示IL-17C与其他促炎信号相结合会导致牛皮癣形状皮肤皮炎的发展。顺便说一句，这些观察结果表明IL-17C是IL-17家族的快速响应成员，并且它协同激活KCS，内皮和TH17/22细胞之间的促炎反馈环，并且在牛皮癣中可能至关重要。我们将使用这种创新的新鼠标模型，遗传敲除方法，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，以测试：IL-17C IL-17C IL-17RE/A ON AN靶细胞在目标细胞上的假设，并结合了22），并结合了22）。与IL-17C协同诱导KC激活和表皮增生。我们打算将IL-17C识别为启动和维持慢性皮肤感染所需的关键早期上游促炎细胞因子，并确定影响的关键细胞靶标通过IL-17C以及用于指导KC，EC和TH17/22细胞反应的潜在机制，这些反应转化为牛皮癣的持续注射和棘突。这项工作将为未来的工作提供基础和理由，以探索针对IL-17C或IL-17RE用于治疗牛皮癣的治疗开发的潜力。