Neurogenic inflammation and psoriasiform dermatitis

神经源性炎症和牛皮癣样皮炎

• 批准号: 8706044
• 负责人: Nicole Leanne Ward
• 金额: $ 20.21万
• 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: 2013-07-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706044
• 关键词: Acanthosis; Accounting; Address; Affect; Botulinum Toxins; CD4 Positive T Lymphocytes; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Case Study; Cell Communication; Cell Differentiation process; Cell Proliferation; Cells; Chemotactic Factors; Coupled; Cutaneous; Data; Dendritic Cells; Denervation; Diabetes Mellitus; Dorsal; Drug Targeting; Hyperplasia; Hypertension; ITGAX gene; Imiquimod; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Knowledge; Leukocytes; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nerve; Nerve Fibers; Nervous system structure; Neurogenic Inflammation; Neuropeptides; Operative Surgical Procedures; Outcome; Pathogenesis; Peptides; Phenotype; Production; Psoriasiform Dermatitis; Psoriasis; Quality of life; Reporting; Resolution; Role; Severity of illness; Skin; Spontaneous Remission; Stress; Substance P; System; T cell response; T-Lymphocyte; Transgenic Organisms; Translating; Transplantation; Work; afferent nerve; base; cell motility; cellular targeting; cytokine; design; diphtheria toxin receptor; human disease; in vivo; inhibitor/antagonist; innovation; insight; intradermal injection; keratinocyte; migration; nerve injury; novel; novel therapeutics; prevent; public health relevance; receptor binding; reconstitution; relating to nervous system; response; skin disorder; skin lesion; therapeutic development

DESCRIPTION (provided by applicant): Psoriatic skin contains more nerve fibers and increased levels of sensory nerve-derived calcitonin gene related peptide (CGRP) and substance P (SP). Interestingly, several case reports have demonstrated psoriatic plaque resolution following accidental skin denervation, and subsequent loss of nerve-derived factors. These results imply a role for the nervous system in maintaining and exacerbating the psoriasis phenotype; however the role and contribution of nerves to the cellular and molecular mechanisms mediating cutaneous inflammation and hyperplasia remains poorly defined. Recent work from our group has identified increases in cutaneous nerve fibers and nerve-derived SP and CGRP in the KC-Tie2 murine model of psoriasiform dermatitis providing an experimental paradigm to explore neural contributions to psoriasis pathogenesis. Following surgical elimination of all nerve fibers entering dorsal skin of KC-Tie2 mice, a 40% decrease in CD11c+ dendritic cells (DCs) was observed beginning 1 day (d) following surgery, followed by a 30% improvement in acanthosis by 7d and a 30% decrease in CD4+ T cells by 10d. These outcomes were SP and CGRP dependent; as reconstitution of SP and CGRP in denervated KC-Tie2 skin prevented phenotype improvement and inhibition of SP and CGRP in innervated KC-Tie2 skin recapitulated the findings elicited by experimental denervation in a neuropeptide specific manner. Similar levels of improvement were observed following one intradermal injection of Botulinum toxin A, a well characterized inhibitor of nerve-derived CGRP/SP. Together these results identify nerve-derived SP and CGRP as critical mediators of psoriasisform skin inflammation, and offer a potential mechanism explaining case and anecdotal reports of nerve-dependent clearing, and provide a unique and innovative opportunity for identifying new therapeutic avenues. To identify the cellular targets affected by nerve-derived SP and CGRP as well as the potential mechanism(s) used to direct KCs, DCs and T cell response that translates to sustaining inflammation and acanthosis in psoriasis, we propose to: (1) stimulate KCs, DCs or T cells in vitro with SP or CGRP and quantitate changes in cell proliferation and differentiation, leukocyte migration and the production of DC- and T cell-derived cytokines and KC-derived leukocyte chemoattractants, in the presence/absence of pharmacological inhibitors of SP and CGRP; and (2) alter SP and CGRP direct effects on KCs and skin- derived immune cells using a combination of transgenic and skin transplant strategies designed to compartmentalize skin specific immunomodulatory responses utilizing T cell-deficient mice and diphtheria toxin receptor inducible DC-depleted mice coupled to SP- and CGRP-receptor deficient mice. The information gained from our studies will identify the cellular targets affecte by nerve-derived SP and CGRP as well as the potential mechanism(s) used to direct KCs, DCs and T cell response that translates to sustaining inflammation and acanthosis in psoriasis.

描述（由申请人提供）：银屑病皮肤含有更多的神经纤维和增加水平的感觉神经源性降钙素基因相关肽（CGRP）和P物质（SP）。有趣的是，一些病例报告表明，意外皮肤去神经支配以及随后神经源性因子的丧失后，银屑病斑块得以消退。这些结果表明神经系统在维持和加剧牛皮癣表型方面发挥着作用；然而，神经在介导皮肤炎症和增生的细胞和分子机制中的作用和贡献仍然不明确。我们小组最近的工作发现，在牛皮癣样皮炎的 KC-Tie2 小鼠模型中，皮肤神经纤维以及神经源性 SP 和 CGRP 有所增加，为探索神经对牛皮癣发病机制的贡献提供了实验范例。手术消除进入 KC-Tie2 小鼠背部皮肤的所有神经纤维后，从手术后 1 天 (d) 开始，观察到 CD11c+ 树突状细胞 (DC) 减少 40%，随后 7 天棘皮症改善 30%，10 天 CD4+ T 细胞减少 30%。这些结果取决于 SP 和 CGRP；去神经支配的 KC-Tie2 皮肤中 SP 和 CGRP 的重建阻止了表型改善，而神经支配的 KC-Tie2 皮肤中 SP 和 CGRP 的抑制概括了以神经肽特异性方式进行实验去神经支配所引起的发现。皮内注射 A 型肉毒杆菌毒素（一种经过充分表征的神经源性 CGRP/SP 抑制剂）后，观察到了类似水平的改善。这些结果共同确定了神经源性 SP 和 CGRP 是银屑病样皮肤炎症的关键介质，并提供了解释神经依赖性清除的病例和轶事报告的潜在机制，并为确定新的治疗途径提供了独特和创新的机会。 为了确定受神经源性 SP 和 CGRP 影响的细胞靶标以及用于指导 KC、DC 和 T 细胞反应（转化为银屑病持续炎症和棘皮症）的潜在机制，我们建议：（1）在体外用 SP 或 CGRP 刺激 KC、DC 或 T 细胞，并定量细胞增殖和分化、白细胞迁移和生成的变化。 DC 和 T 细胞衍生的细胞因子以及 KC 衍生的白细胞趋化剂，存在/不存在 SP 和 CGRP 药理学抑制剂的情况下； (2) 使用转基因和皮肤移植策略相结合，改变 SP 和 CGRP 对 KC 和皮肤源性免疫细胞的直接影响，该策略旨在利用 T 细胞缺陷小鼠和白喉毒素受体诱导性 DC 耗尽小鼠与 SP 和 CGRP 受体缺陷小鼠偶联来划分皮肤特异性免疫调节反应。 从我们的研究中获得的信息将确定受神经源性 SP 和 CGRP 影响的细胞靶标，以及用于指导 KC、DC 和 T 细胞反应的潜在机制，从而转化为牛皮癣中持续的炎症和棘皮症。