Mechanisms of sensory neuron control over skin immune responses

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。虽然已经确定了几个关键的细胞和细胞因子途径对银屑病病理学至关重要，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，用Toll样受体激动剂局部治疗皮肤，其在生理上模拟 自身核酸的释放和/或病毒感染已显示在小鼠中导致银屑病样病理。使用这个模型，我们令人兴奋的初步数据表明，皮肤中的感觉神经支配作为皮肤免疫病理学的煽动者和促进者起着关键作用。因此，该提案的具体目标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，特别是在银屑病模型的背景下。由于最近描述的重要性，真皮？在这个模型中的T细胞，是皮肤驻留的细胞亚群，并对细胞因子信号做出快速反应，我们假设感觉神经元可能直接或间接与？T细胞以调节其功能。这项提案的第一个目标将寻求表征感觉去神经支配如何改变皮肤？T细胞表型和功能。基于从Aim 1收集的数据和从文献中收集的几个有趣的线索，Aim 2将研究从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，这些因子是已知的？T细胞。这两个互补目标的成功完成将提供一个机制的理解，感觉神经元如何控制一系列的免疫介质最终在真皮？T细胞活化与银屑病皮损的临床相关性。解开组织内神经免疫相互作用的复杂网络，其通常参与导致严重和衰弱疾病的错误免疫应答，将为皮肤病的免疫调节提供新的治疗靶点。在某些情况下，如接种疫苗，更好地了解控制T细胞命运决定的线索将有助于设计可以促进皮肤驻留和保护记忆的疫苗。最后，由于？T细胞源性细胞因子在中性粒细胞募集中的作用 对抗皮肤感染，如金黄色葡萄球菌，了解激活的内源性触发因素？T细胞将导致潜在的新颖和前所未有的疗法，用于治疗宿主防御受损的持续感染。 公共卫生相关性：免疫驱动的病理性皮肤病，如牛皮癣，可能会严重衰弱，并影响许多人。目前缺乏针对非广泛免疫抑制的皮肤病的特异性治疗，因此这些治疗可能导致机会性感染的并发症。该项目旨在研究皮肤中的感觉神经元如何与免疫系统沟通，以协调免疫病理学，从而发现治疗炎症性皮肤病（如银屑病）的新的、潜在的特异性靶点。

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. PUBLIC HEALTH RELEVANCE: Immune-driven pathological skin conditions such as psoriasis can be severely debilitating and affect many individuals. There is currently a lack of specific treatments for skin diseases that are not broadly immunosuppressive and as a result these therapies can lead to complications from opportunistic infections. This project seeks to investigate how sensory neurons in the skin communicate with the immune system in order to orchestrate immunopathology and as a result will uncover new, and potentially specific, targets for the treatment of inflammatory skin diseases such as psoriasis.