Protective role of Clec7a/dectin-1 in CNS autoimmunity

项目概要/摘要 多发性硬化症（MS）被认为是一种T细胞介导的自身免疫性疾病， 最初的先天免疫活性和神经变性之间的关系仍然知之甚少。在这个项目中， 我们的目的是阐明dectin-1，一种C型凝集素受体（dectin-1）的新的保护作用是如何通过以下途径发挥作用的： 实验性大鼠中枢神经系统（CNS）浸润的髓样细胞与CNS驻留细胞的串扰 自身免疫性脑脊髓炎（EAE）和铜腙诱导的脱髓鞘（CID）模型。Dectin-1已被 最深入研究的先天免疫受体之一，检测真菌细胞壁以诱导炎症。 然而，我们最近发现dectin-1在EAE中是一种保护性分子，并且dectin-1在EAE中的保护作用可能与dectin-1的表达有关。 神经炎症尚未定义。特别是，dectin-1在MS/EAE中的作用完全未知。我们 初步数据也强烈表明，至少在星形胶质细胞上表达的内源性分子， dectin-1的保护作用。 本项目的目标是描述先天免疫活动如何导致EAE的神经保护。基于 根据我们的初步数据，我们的中心假设是：髓样细胞通过 dectin-1介导免疫系统和CNS之间的串扰，促进神经保护。本研究 将有助于越来越多的证据表明，dectin-1的重要性超出了真菌感染的范围。 我们通过确定Dectin-1的一种新的保护机制，特别是在 CNS自身免疫和神经变性的背景。该项目将引起对dectin-1的考虑， 其效应子功能超出感染范围，为治疗干预提供潜在的新靶点 神经炎性疾病

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease, and the relationship between initial innate immune activity and neurodegeneration is still poorly understood. In this proposed project, we aim to elucidate how the novel protective role of dectin-1, a C-type lectin receptor (CLR), is exerted through crosstalk of myeloid cells infiltrated in the central nervous system (CNS) and CNS-resident cells in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination (CID) models. Dectin-1 has been one of the most intensively studied innate immune receptors, detecting fungal cell wall to induce inflammation. However, we recently found that dectin-1 is a protective molecule in EAE, and the protective role of dectin-1 in neuroinflammation has not been defined. In particular, the role of dectin-1 in MS/EAE is entirely unknown. Our preliminary data also strongly suggested that endogenous molecules, expressed at least on astrocytes, trigger the protective role of dectin-1. The goal of this project is to delineate how innate immune activities lead to neuroprotection in EAE. Based on our preliminary data, our central hypothesis is: Myeloid cells sense endogenous inflammatory cues through dectin-1 to mediate crosstalk between the immune system and CNS that promotes neuroprotection. This study will contribute to a growing body of evidence that dectin-1 has importance beyond the context of fungal infection. We advance this emerging understanding by identifying a new protective mechanism of Dectin-1, specifically in the setting of CNS autoimmunity and neurodegeneration. This project will provoke consideration of dectin-1 and its effector functions beyond the context of infection to provide potential novel targets for therapeutic intervention in neuroinflammatory disorders.