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

多发性硬化症(MS)是一种中枢神经系统(CNS)炎症性脱髓鞘疾病，是 西方年轻人中非创伤性神经功能障碍的最常见原因 半球。疾病修正疗法(DMT)的开发已取得重大进展 通过阻断或消耗病原体来降低临床多发性硬化症复发的频率 淋巴细胞。然而，批准的DMT没有一种是治愈的，也没有一种对所有患者有效。那里 没有任何治疗方法可以减缓或逆转多发性硬化症的进展形式。目前的提议是基于 认为髓系细胞和调节它们的因素应该被视为候选细胞 治疗目前无反应的复发或进展型多发性硬化症的治疗目标 已使用DMT。髓系细胞(包括巨噬细胞、树突状细胞和小胶质细胞)是主要成分。 多发性硬化症患者和实验性自身免疫小鼠中神经炎性细胞浸润的研究 脑脊髓炎(EAE)，被广泛用作MS的动物模型。髓系细胞的异常 这项提案的总体目标是 研究中枢神经系统(CNS)内积聚的髓系细胞的特征 自身免疫性脱髓鞘病的不同阶段。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M1细胞和修复性M2细胞 表达精氨酸酶-1(Arg1)的基因。我们的初步研究表明，中枢神经系统浸润性髓样细胞的表型 细胞随着EAE的进展和缓解而演变。在临床前阶段，有相当比例的 中枢神经系统髓系细胞表达iNOS，但无Arg1表达。临床发作时，iNOS Arg1双阳性和 中枢神经系统内可见Arg1单一阳性髓系细胞。当小鼠进入缓解期时，只有Arg1 单个阳性的髓系细胞仍然存在。在目标1中，我们将使用一组基因工程小鼠来阐明 在EAE期间炎症的中枢神经系统中驱动iNOS和Arg1髓系细胞极化的途径。在AIMS中 2和3我们将描述中枢神经系统浸润性髓样细胞的转录和生物学特性 亚集，并确定耗尽、扭曲或阻断 Arg1和iNOS CNS髓系细胞的功能。在目标4中我们将研究密度和 活动性、慢性活动性和复发性多发性硬化患者尸检中髓系细胞亚群的分布 人脑切片。我们希望这项研究将最终导致新型MS的发展 抑制致病髓系亚群，同时增强修复亚群的治疗，目标是 复发-缓解和进展型MS患者的残疾减轻，甚至逆转。

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.