Arginase-1 and iNOS expressing CNS myeloid cell subsets in EAE and MS

多发性硬化症（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病， 在西方，非创伤性神经功能障碍的最常见原因是 半球疾病修饰疗法（DMT）的发展取得了重大进展 通过阻断或消除致病性的， 淋巴细胞然而，没有一种被批准的DMT是治愈性的，也没有一种对所有患者都有效。那里 没有治疗方法可以减缓或逆转MS的进展形式。目前的建议是基于 骨髓细胞和调节它们的因子应该被认为是候选者的论点 用于治疗复发或进行性形式的MS的治疗靶点，所述MS对目前的药物治疗无反应， 使用DMT。髓样细胞（包括巨噬细胞、树突状细胞和小胶质细胞）构成主要成分 MS患者和实验性自身免疫小鼠中神经炎性浸润的 脑脊髓炎（EAE，广泛用作MS的动物模型）。骨髓细胞的脱落已经被 记录在复发-缓解型和进展型MS中。本提案的总体目标是 研究在中枢神经系统（CNS）中积累的髓样细胞的特征， 自身免疫性脱髓鞘疾病的不同阶段骨髓来源的巨噬细胞已经广泛地 分类为表达诱导型一氧化氮合酶（iNOS）的促炎性M1细胞和修复性M2细胞 表达精氨酸酶-1（Arg 1）。我们的初步研究表明，CNS浸润性髓样细胞的表型 细胞随着EAE的进展和缓解而进化。在临床前阶段， 的CNS髓样细胞表达iNOS，但均不表达Arg 1。在临床发病时，iNOS+ Arg 1+双阳性和 Arg 1+单个阳性髓样细胞出现在CNS浸润中。当小鼠进入缓解期时，只有Arg 1 + 单个阳性髓样细胞保留。在目标1中，我们将使用一组基因工程小鼠来阐明 在EAE期间驱动炎症CNS中iNOS+与Arg 1+骨髓细胞极化的途径。目标 图2和图3中，我们将描述CNS浸润髓样细胞的转录组和生物学特性。 亚群，并确定耗尽，偏斜或阻断的临床和病理后果， Arg 1+或iNOS+ CNS髓样细胞的功能。在目标4中，我们将研究密度和 尸检中一组活动性、慢性活动性和复发性MS病变中骨髓细胞亚群的分布 人脑切片我们希望这项研究将最终导致新的MS的发展 抑制致病性骨髓亚群，同时增强修复性亚群的疗法，目的是 缓解甚至逆转复发缓解型和进展型MS患者的残疾。

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), is the most common cause of non-traumatic neurological disability in young adults in the Western Hemisphere. Significant progress has been made in the development of disease modifying therapies (DMT) that decrease the frequency of clinical MS relapses by blocking or depleting pathogenic lymphocytes. However, none of the approved DMT are curative, and none are effective in all patients. There are no treatments that slow, or reverse, progressive forms of MS. The current proposal is based on the contention that myeloid cells, and the factors that modulate them, should be considered as candidate therapeutic targets for the treatment of relapsing or progressive forms of MS that are unresponsive to currently used DMT. Myeloid cells (including macrophages, dendritic cells and microglia) comprise a major component of the neuroinflammatory infiltrates in patients with MS and in mice with experimental autoimmune encephalomyelitis (EAE, widely used as an animal model of MS). Abnormalities of myeloid cells have been documented in relapsing-remitting as well as progressive forms of MS. The overall goal of this proposal is to investigate the characteristics of the myeloid cells that accumulate in the central nervous system (CNS) during different stages of autoimmune demyelinating disease. Bone marrow derived macrophages have been broadly classified as pro-inflammatory M1 cells that express inducible nitric synthase (iNOS), and reparative M2 cells that express arginase-1 (Arg1). Our preliminary studies show that the phenotypes of CNS-infiltrating myeloid cells evolve with the progression and remission of EAE. During the preclinical stage, a significant percentage of CNS myeloid cells express iNOS, but none express Arg1. At clinical onset, iNOS+Arg1+ double positive and Arg1+ single positive myeloid cells appear in CNS infiltrates. As mice enter the remission phase only Arg1+ single positive myeloid cells remain. In Aim 1 we will use a panel of genetically engineered mice to elucidate the pathways that drive iNOS+ versus Arg1+ myeloid cell polarization in the inflamed CNS during EAE. In Aims 2 and 3 we will characterize the transcriptomes and biological properties of the CNS-infiltrating myeloid subsets, and determine the clinical and pathological consequences of depleting, skewing or blocking the functions of Arg1+ or iNOS+ CNS myeloid cells, respectively. In Aim 4 we will investigate the density and distribution of myeloid cell subsets in a panel of active, chronic active and relapsing MS lesions in autopsied human brain sections. We are hopeful that this research will ultimately lead to the development of novel MS therapies that suppress pathogenic myeloid subsets, while enhancing reparative subsets, with the goal of mitigating, and even reversing, disability in individuals with relapsing-remitting and progressive forms of MS.