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）的炎性脱髓鞘疾病，是西方年轻人的非创伤性神经残疾的最常见原因半球。在改变疾病疗法（DMT）方面已经取得了重大进展通过阻断或耗尽致病性，降低了临床MS的复发频率淋巴细胞。但是，批准的DMT均未治愈，并且在所有患者中都没有有效。那里不是慢慢或反向MS的渐进形式的治疗方法。当前的提议是基于认为髓样细胞以及调节它们的因素应被视为候选者用于治疗复发或进行渐进形式的MS的治疗靶标，这些目标对当前没有反应使用的DMT。髓样细胞（包括巨噬细胞，树突状细胞和小胶质细胞）包括主要成分 MS和具有实验性自身免疫的小鼠的患者的神经炎症性浸润脑脊髓炎（EAE，广泛用作MS动物模型）。髓样细胞的异常已经记录在复发式变形以及MS的渐进形式中。该提议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。骨髓衍生的巨噬细胞已广泛归类为表达诱导型一氮合酶（INOS）和修复M2细胞的促炎性M1细胞那个表达精氨酸酶-1（arg1）。我们的初步研究表明，CNS渗透髓样的表型细胞随着EAE的进展和缓解而发展。在临床前阶段，很大的百分比 CNS髓样细胞表达iNOS，但没有任何表达arg1。在临床发作时，iNOS+ arg1+双阳性和 ARG1+单个阳性髓样细胞出现在中枢神经系统浸润中。当小鼠进入缓解阶段时，ARG1+ 单个阳性髓样细胞保留。在AIM 1中，我们将使用一组基因工程小鼠来阐明 EAE期间发炎的CNS中驱动iNOS+与arg1+髓样细胞极化的途径。在目标中 2和3我们将表征CNS浸润髓样的转录组和生物学特性子集，并确定耗尽，歪曲或阻塞的临床和病理后果 Arg1+或Inos+ CNS髓样细胞的功能。在AIM 4中，我们将研究密度和骨髓细胞子集的分布在载opopopied中的活性，慢性活动和复发的MS病变中的分布人脑切片。我们希望这项研究最终将导致新颖的MS的发展抑制致病性髓样子集的疗法，同时增强了修复子集，目的是 MS的复发和渐进形式的个体中的残疾，减轻甚至逆转。

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.