Mechanisms of sensory neuron control over skin immune responses

感觉神经元控制皮肤免疫反应的机制

基本信息

批准号：
8521056
负责人：
Jose Manuel Ordovas-Montanes
金额：
$ 3.39万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8521056
关键词：
Adjuvant Affect Afferent Neurons Agonist Aryl Hydrocarbon Receptor Automobile Driving Biological Assay Biological Availability Biological Response Modifiers Cell Count Cell physiology Cells Complex Cues Cutaneous Cytokine Signaling Data Denervation Dermal Dinoprostone Disease Experimental Models Generations Genes Goals Homeostasis Host Defense Imiquimod Immune Immune response Immune system Immunity Immunosuppressive Agents In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-17 Internet Lead Lesion Link Literature Mediating Mediator of activation protein Memory Modeling Molecular Mus Myeloid Cells Nucleic Acids Opportunistic Infections Pathology Pathway interactions Phenotype Production Psoriasis Publications Publishing RNA Interference Recruitment Activity Role Sensory Skin Staphylococcus aureus Stimulus Substance P Surface System T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TLR7 gene TNF gene Testing Tissues Toll-like receptors Vaccination Vaccine Design Vaccines Virus Diseases aryl hydrocarbon receptor ligand base clinically relevant combat cytokine direct application immunopathology immunoregulation in vivo inhibitor/antagonist interleukin-22 interleukin-23 intradermal injection nerve supply neutrophil new therapeutic target novel promoter public health relevance release factor research study skin disorder

项目摘要

DESCRIPTION (provided by applicant): Psoriasis and other pathological skin diseases have typically been considered as immune-driven diseases. While several key cellular and cytokine pathways have been identified that are critical to psoriasis pathology, many mechanisms still remain unknown particularly due to the lack of good experimental models for psoriasis. Recently, topical treatment of skin with a toll-like receptor agonist, which physiologically mimics the release of self-nucleic acids and/or viral infection, has been shown to result in psoriasis-lik pathology in mice. Using this model, our exciting preliminary data suggests a critical role for sensory innervation in the skin as an instigator and promoter of skin immunopathology. As a result, the specific aims of this proposal will aim to mechanistically link how sensory neurons control immune responses in the skin, particularly within the context of a model of psoriasis. Due to the recent description of the importance of dermal ?¿ T cells in this model, a subset of cells that is skin-resident and primed to respond rapidly to cytokine signals, we hypothesize that sensory neurons may directly or indirectly communicate with ?¿ T cells in order to regulate their function. The first aim of this proposal will seek to characterize how sensory denervation alters dermal ?¿ T cell phenotype and function. Based on the data gathered from Aim 1 and several intriguing clues gathered from the literature, Aim 2 will investigate how known factors released from sensory neurons regulate the production of cytokines and mediators which are known triggers of ?¿ T cells. The successful completion of these two complementary aims will provide a mechanistic understanding of how sensory neurons control a cascade of immune mediators culminating in dermal ?¿ T cell activation and, of clinical relevance, the generation of psoriatic lesions. Unraveling the complex web of neuro-immune interactions within a tissue that is commonly involved in misdirected immune responses resulting in severe and debilitating disease will provide novel therapeutic targets for immunomodulation of skin disease. In some situations, such as vaccination, a better understanding of the cues which control T-cell fate decisions will help to design vaccines that can promote memory that is both skin-resident and protective. Finally, due to the importance of ?¿ T cell-derived cytokines in recruiting neutrophils to combat cutaneous infections, such as Staphylococcus aureus, an understanding of the endogenous triggers which activate ?¿ T cells will lead to potentially novel and unprecedented therapies for the treatment of ongoing infections where host defense is compromised.

描述（由申请人提供）：银屑病和其他病理性皮肤病通常被认为是免疫驱动的疾病，虽然已经确定了对银屑病病理学至关重要的几种关键细胞和细胞因子途径，但许多机制仍然未知，特别是由于缺乏。最近，使用 Toll 样受体激动剂对皮肤进行局部治疗，其生理学模拟。自身核酸的释放和/或病毒感染已被证明会导致小鼠出现银屑病样病理，使用该模型，我们令人兴奋的初步数据表明，皮肤感觉神经支配作为银屑病的煽动者和促进者发挥着关键作用。因此，该提案的具体目标是从机制上联系感觉神经元如何控制皮肤的免疫反应，特别是在牛皮癣模型的背景下。真皮？??该模型中的 T 细胞是皮肤驻留细胞的一个子集，能够对细胞因子信号快速做出反应，我们研究感觉神经元可能直接或间接与？为了调节 T 细胞的功能，该提案的第一个目标将寻求表征感觉去神经支配如何改变真皮？ T 细胞表型和功能根据目标 1 收集的数据和从文献中收集的一些有趣的线索，目标 2 将研究感觉神经元释放的已知因子如何调节细胞因子和介质的产生，这些细胞因子和介质是已知的触发因素。 T 细胞成功完成这两个互补的目标将为感觉神经元如何控制一系列免疫介质最终在真皮中提供机制理解。 T 细胞的激活以及具有临床意义的银屑病病变的产生，揭示了组织内神经免疫相互作用的复杂网络，这种相互作用通常涉及导致严重和衰弱疾病的错误免疫反应，将为皮肤免疫调节提供新的治疗靶点。在某些情况下，例如疫苗接种，更好地了解控制 T 细胞命运决定的线索将有助于设计能够促进皮肤驻留和保护性记忆的疫苗。 T 细胞衍生的细胞因子在募集中性粒细胞中的作用为了对抗皮肤感染，例如金黄色葡萄球菌，了解激活的内源性触发因素？ T 细胞将带来潜在的新颖且前所未有的疗法，用于治疗宿主防御受损的持续感染。