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

• 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
• 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

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（由适用提供）：牛皮癣和其他病理皮肤疾病通常被认为是免疫驱动的疾病。尽管已经鉴定出了几种对牛皮癣病理至关重要的关键细胞和细胞因子途径，但许多机制仍然未知，尤其是由于缺乏牛皮癣的良好实验模型。最近，用Toll样受体激动剂对皮肤的局部治疗，它在物理上模仿 自核酸和/或病毒感染的释放已被证明会导致小鼠的牛皮癣病理学。使用此模型，我们令人兴奋的初步数据表明，作为皮肤免疫病理学的刺激器和启动子，皮肤的感觉神经神经的关键作用。结果，该提案的具体目的将旨在机械地联系感觉神经元如何控制皮肤中的免疫反应，尤其是在牛皮癣模型的背景下。在该模型中，最新描述了真皮细胞的重要性，这是皮肤驻留并启动对细胞因子信号迅速反应的细胞的子集，我们假设感觉神经元可以直接或间接与T细胞进行直接或间接沟通以调节其功能。该提案的第一个目的将试图表征感觉神经化性如何改变皮肤的表型和功能。基于从AIM 1收集的数据以及从文献中收集的几个有趣的簇，AIM 2将研究从感觉神经元中释放的已知因素如何调节细胞因子和介体的产生，这些细胞因子和介体是已知的触发触发器的触发器。这两个完整目标的成功完成将提供机械理解，即感觉神经元如何控制一系列免疫介质的级联，最终导致皮细胞激活以及临床相关性，是银屑病病变的产生。在组织中揭示复杂的神经免疫相互作用的复杂网络，该组织通常涉及误导的免疫调查，从而导致严重且令人衰弱的疾病，这将为皮肤疾病的免疫调节提供新颖的治疗靶标。在某些情况下，例如疫苗，对控制T细胞命运决策的线索有更好的了解将有助于设计可以促进既居住又受保护的记忆的疫苗。最后，由于？t细胞衍生的细胞因子在募集中性粒细胞中的重要性 为了对抗皮肤病的皮肤感染，例如金黄色葡萄球菌，了解激活T细胞的内源性触发因素将导致潜在的新型和前所未有的疗法，以治疗宿主防御的正在进行的感染。