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，感觉神经源性降钙素基因相关肽（CGRP）和P物质（SP）水平升高。有趣的是，一些病例报告已经证明了意外皮肤去神经后银屑病斑块消退，以及随后神经源性因子的丧失。这些结果表明神经系统在维持和加重银屑病表型中的作用;然而，神经对介导皮肤炎症和增生的细胞和分子机制的作用和贡献仍然不清楚。我们小组最近的工作已经确定了增加皮肤神经纤维和神经源性SP和CGRP的KC-Tie 2银屑病样皮炎小鼠模型提供了一个实验范例，探索神经的贡献银屑病发病机制。在手术消除进入KC-Tie 2小鼠背部皮肤的所有神经纤维后，在手术后第1天（d）开始观察到CD 11 c+树突状细胞（DC）减少40%，随后到第7天棘皮病改善30%，到第10天CD 4 + T细胞减少30%。这些结果是SP和CGRP依赖性的;由于去神经支配的KC-Tie 2皮肤中SP和CGRP的重建阻止了表型改善，并且神经支配的KC-Tie 2皮肤中SP和CGRP的抑制概括了以神经肽特异性方式通过实验性去神经支配引起的发现。类似的改善水平，观察到一个皮内注射肉毒毒素A，一个很好的特征抑制剂神经源性CGRP/SP。这些结果一起确定神经源性SP和CGRP作为银屑病样皮肤炎症的关键介质，并提供了一个潜在的机制解释的情况下和轶事报告的神经依赖性清除，并提供了一个独特的和创新的机会，以确定新的治疗途径。 为了鉴定受神经源性SP和CGRP影响的细胞靶点以及用于指导KC、DC和T细胞应答的潜在机制，其转化为银屑病中持续的炎症和棘皮症，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的变化，在存在/不存在SP和CGRP的药理学抑制剂的情况下，白细胞迁移以及DC和T细胞衍生的细胞因子和KC衍生的白细胞化学引诱物的产生;（2）改变SP和CGRP对KCs和皮肤的直接作用。使用转基因和皮肤移植策略的组合衍生的免疫细胞利用T细胞缺陷型小鼠和白喉毒素受体诱导型DC耗尽型小鼠与SP-和CGRP-受体缺陷型小鼠偶联。 从我们的研究中获得的信息将确定受神经源性SP和CGRP影响的细胞靶点，以及用于指导KC、DC和T细胞应答的潜在机制，这些机制转化为银屑病中持续的炎症和棘皮症。