Protective role of Clec7a/dectin-1 in CNS autoimmunity

项目摘要/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，与 最初的先天免疫活动和神经退行性变之间的关系仍然知之甚少。在这个拟议的项目中， 我们旨在阐明C型凝集素受体(CLR)Dectin-1的新的保护作用是如何通过 实验性中枢神经系统髓系细胞和中枢神经驻留细胞的串扰 自身免疫性脑脊髓炎(EAE)和铜吡酮诱导的脱髓鞘(CID)模型。Dectin-1已经被 研究最深入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中是一种保护分子，并且Dectin-1在EAE中的保护作用。 神经炎症的定义还没有确定。特别是，Dectin-1在MS/EAE中的作用完全未知。我们的 初步数据还强烈表明，至少在星形胶质细胞上表达的内源性分子会触发 Dectin-1的保护作用。 这个项目的目标是描绘先天免疫活动如何导致EAE的神经保护。基座 根据我们的初步数据，我们的中心假设是：髓系细胞通过 Dectin-1调节免疫系统和促进神经保护的中枢神经系统之间的串扰。本研究 将有助于越来越多的证据表明Dectin-1在真菌感染之外具有重要意义。 我们通过确定Dectin-1的一种新的保护机制来推动这一新的理解，特别是在 中枢神经系统自身免疫和神经退行性变的发生。该项目将引起对DECIN-1和 其效应器的功能超越了感染环境，为治疗干预提供了潜在的新靶点 在神经炎性疾病中。

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.