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

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

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中文摘要
翻译
多发性硬化症(MS)是一种中枢神经系统(CNS)的炎症性脱髓鞘疾病
英文摘要
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.
期刊论文(4)
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科研奖励(0)
会议论文
DOI: 10.4049/jimmunol.2000797
发表时间: 2021-01-01
期刊: Journal of immunology (Baltimore, Md. : 1950)
影响因子: --
作者: [Mockus TE, Munie A, Atkinson JR, Segal BM]
通讯作者: Segal BM
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.
FASEB SRC: The Translational Neuroimmunology Conference: From Bench to Bedside and Back
A novel inflammatory cell with neuroprotective and neuroregenerative properties
  • 批准号:
    10391439
  • 项目类别:
  • 资助金额:
    $26.36万
  • 财政年份:
    2018
  • 负责人:
    Benjamin M Segal
  • 依托单位:
A novel inflammatory cell with neuroprotective and neuroregenerative properties
  • 批准号:
    9900003
  • 项目类别:
  • 资助金额:
    $27.88万
  • 财政年份:
    2018
  • 负责人:
    Benjamin M Segal
  • 依托单位:
The mechanism of action of Granulocyte Macrophage-Colony Stimulating Factor in an animal model of Multiple Sclerosis
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