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（由申请人提供）：牛皮癣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，特别是由于缺乏良好的银屑病实验模型。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。使用这个模型，我们令人兴奋的初步数据表明皮肤感觉神经支配作为皮肤免疫病理学的煽动者和促进者的关键作用。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中的免疫反应，特别是在牛皮癣模型的背景下。由于最近描述了真皮 T 细胞在该模型中的重要性，真皮 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，因此我们假设感觉神经元可能直接或间接与 T 细胞通信，以调节其功能。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 收集的数据以及从文献中收集的一些有趣线索，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 T 细胞的已知触发因素。这两个互补目标的成功完成将为感觉神经元如何控制一系列免疫介质最终导致真皮 T 细胞激活以及临床相关的银屑病病变的产生提供机制理解。解开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，将为皮肤病的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。最后，由于 T 细胞衍生的细胞因子在招募中性粒细胞中的重要性 为了对抗金黄色葡萄球菌等皮肤感染，了解激活 T 细胞的内源性触发因素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。