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

EAE 和 MS 中表达精氨酸酶 1 和 iNOS 的 CNS 骨髓细胞亚群

基本信息

批准号：
10221066
负责人：
Benjamin M Segal
金额：
$ 35.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221066
关键词：
Abnormal Myeloid Cell Address Adoptive Transfer Animal Model Antibodies Area Autoimmune Autopsy Biological Biological Markers Biological Process Blood Blood - brain barrier anatomy Bone Marrow Brain CD4 Positive T Lymphocytes Cells Characteristics Chronic Clinical Demyelinating Diseases Dendritic Cells Development Disease Disease remission Evolution Experimental Autoimmune Encephalomyelitis Frequencies Future Genetic Genetically Engineered Mouse Goals Heterogeneity Human Immune Immunologics In Vitro Individual Inflammatory Knockout Mice Lead Lesion Lymphocyte Metachromatic Leukodystrophy Microglia Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelogenous Myeloid Cells Neuraxis Neurologic Neurologic Deficit Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Phase Phenotype Progressive Multifocal Leukoencephalopathy Property Relapse Reporter Research Role Spatial Distribution Spleen Stains Time Tissues arginase base central nervous system demyelinating disorder curative treatments density disability inducible gene expression inflammatory milieu insight lymph nodes macrophage monocyte multiple sclerosis patient nervous system disorder neuroinflammation novel novel therapeutics polarized cell pre-clinical repaired therapeutic candidate therapeutic target transcription factor transcriptome white matter young adult

项目摘要

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.

多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 炎症性脱髓鞘疾病西方年轻人非创伤性神经功能障碍的最常见原因半球。疾病修饰疗法（DMT）的开发取得了重大进展通过阻断或消除致病菌来降低临床多发性硬化症复发的频率淋巴细胞。然而，所有已批准的 DMT 都没有治愈性，也没有一种对所有患者都有效。那里没有任何治疗方法可以减缓或逆转进展型多发性硬化症。目前的提案基于认为骨髓细胞及其调节因子应被视为候选细胞的争论治疗复发或进行性多发性硬化症的治疗目标，这些治疗对目前的药物无反应使用DMT。骨髓细胞（包括巨噬细胞、树突状细胞和小胶质细胞）是其主要成分 MS 患者和实验性自身免疫小鼠的神经炎症浸润脑脊髓炎（EAE，广泛用作 MS 的动物模型）。骨髓细胞异常记录在复发缓解型和进行性多发性硬化症中。该提案的总体目标是研究在中枢神经系统（CNS）中积累的骨髓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被广泛分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 (Arg1)。我们的初步研究表明，中枢神经系统浸润性骨髓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，很大一部分的 CNS 骨髓细胞表达 iNOS，但不表达 Arg1。临床发病时，iNOS+Arg1+ 双阳性且 Arg1+ 单阳性骨髓细胞出现在中枢神经系统浸润中。当小鼠进入缓解期时，仅 Arg1+ 保留单个阳性骨髓细胞。在目标 1 中，我们将使用一组基因工程小鼠来阐明 EAE 期间，在发炎的 CNS 中驱动 iNOS+ 与 Arg1+ 骨髓细胞极化的途径。目标中在图2和图3中，我们将描述中枢神经系统浸润骨髓的转录组和生物学特性子集，并确定耗尽、扭曲或阻断的临床和病理后果 Arg1+ 或 iNOS+ CNS 骨髓细胞的功能分别。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多发性硬化症病变中骨髓细胞亚群的分布人类大脑切片。我们希望这项研究最终能够促进新型 MS 的发展抑制致病性骨髓亚群，同时增强修复亚群的疗法，其目标是减轻甚至逆转复发缓解型和进行性多发性硬化症患者的残疾。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Encephalitogenic and Regulatory CD8 T Cells in Multiple Sclerosis and Its Animal Models.

DOI：
10.4049/jimmunol.2000797
发表时间：
2021-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Mockus TE;Munie A;Atkinson JR;Segal BM
通讯作者：
Segal BM

Biological aging of CNS-resident cells alters the clinical course and immunopathology of autoimmune demyelinating disease.

DOI：
10.1172/jci.insight.158153
发表时间：
2022-06-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Atkinson, Jeffrey R.;Jerome, Andrew D.;Sas, Andrew R.;Munie, Ashley;Wang, Cankun;Ma, Anjun;Arnold, William D.;Segal, Benjamin M.
通讯作者：
Segal, Benjamin M.