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(申请人提供)：银屑病患者皮肤含有更多神经纤维，感觉神经源性降钙素基因相关肽(CGRP)和P物质(SP)水平增加。有趣的是，几个病例报告显示，银屑病斑块在意外皮肤失神经后消退，随后神经源性因子丢失。这些结果暗示神经系统在维持和加重银屑病表型中的作用；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不清楚。我们小组最近的工作发现，在银屑病样皮炎KC-Tie2小鼠模型中，皮肤神经纤维和神经源性SP和CGRP增加，为探索神经在银屑病发病机制中的作用提供了一个实验范式。在手术清除所有进入KC-Tie2小鼠背部皮肤的神经纤维后，CD11c+树突状细胞(DC)在手术后1天(D)下降了40%，随后棘皮病在7d时改善了30%，CD4+T细胞在10d时减少了30%。这些结果是SP和CGRP依赖的；由于SP和CGRP在失神经支配的KC-Tie2皮肤中的重建阻止了支配KC-Tie2皮肤中SP和CGRP的表型改善和抑制，因此以神经肽特异性的方式概括了实验性去神经支配的结果。皮内注射A型肉毒毒素后，也观察到类似程度的改善，A型肉毒毒素是一种具有良好特征的神经源性CGRP/SP抑制剂。综上所述，这些结果确定神经源性SP和CGRP是银屑病形成皮肤炎症的关键介质，并提供了一种潜在的机制，解释了病例和坊间报道的神经依赖清除，并为寻找新的治疗途径提供了独特的创新机会。为了明确神经源性P物质和降钙素基因相关肽对细胞的作用靶点及其可能的作用机制(S)，我们建议：(1)用P物质或降钙素基因相关肽在体外刺激角质形成细胞、树突状细胞或T细胞，在有无药物抑制剂的情况下，定量细胞增殖和分化、白细胞迁移以及DC和T细胞衍生细胞因子和趋化因子的产生；以及(2)利用转基因和皮肤移植策略的组合，改变SP和CGRP对KCs和皮肤来源免疫细胞的直接影响，这些策略旨在利用T细胞缺陷小鼠和白喉毒素受体诱导的DC耗竭小鼠与SP和CGRP受体缺陷小鼠相结合，将皮肤特异性免疫调节反应区分开来。从我们的研究中获得的信息将确定神经源性SP和CGRP影响的细胞靶点以及用于指导KCs、DC和T细胞反应的潜在机制(S)，该反应转化为银屑病中持续的炎症和棘皮病。