Mechanisms of GM-CSF effect in CNS autoimmune demyelination

GM-CSF在中枢神经系统自身免疫性脱髓鞘中的作用机制

• 批准号: 10062792
• 负责人: A.M. Rostami
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062792
• 关键词: Acute; Animal Model; Antigen-Presenting Cells; Autoimmune; Autoimmune Diseases; B-Lymphocytes; CD4 Positive T Lymphocytes; CNS autoimmunity; Cells; Chronic; Chronic Phase; Colony-Stimulating Factor Receptors; Data; Demyelinations; Dendritic Cells; Development; Disease; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Hematopoietic; Human; In Vitro; Inflammatory; Interleukin-10; Knowledge; Lymphoid Cell; Mediator of activation protein; Microglia; Multiple Sclerosis; Mus; Nerve Regeneration; Pathogenesis; Pathogenicity; Peripheral; Phenotype; Play; Production; Regulatory T-Lymphocyte; Role; Signal Transduction; System; T-Lymphocyte; Testing; Th1 Cells; Therapeutic Effect; Time; Tissues; Transforming Growth Factor beta; base; cellular targeting; cytokine; human model; immunoregulation; in vivo; interleukin-23; macrophage; monocyte; monocyte colony stimulating factor; multiple sclerosis patient; novel; novel therapeutics

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine essential for the development and progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Although GM-CSF is mainly produced by pathogenic Th17 and Th1 cells, GM-CSF receptor (GM-CSFR) is not expressed on T and B cells, but is expressed on antigen-presenting cells (APCs). Among them, Ly6ChiCCR2+ monocytes are essential for the pathogenic role of GM-CSF in EAE. Further, GM- CSF signaling in peripheral, but not CNS cells, plays a vital role in the development of acute EAE. However, whether lack of GM-CSF signaling results in development of immunoregulatory APCs has not been studied, and the role of GM-CSF signaling in CNS cells in EAE chronicity, for which microglia activation plays a major role, remains unknown. Our preliminary results for the first time show enhanced production of immunoregulatory molecules in APCs, and increased IL-10 and Foxp3 expression in CD4+ T cells of mice lacking GM-CSF. Similarly, neutralizing GM-CSF in human monocyte culture results in an increase of IL-27 and TGF-β production. Based on these observations, we hypothesize that GM-CSF induces proinflammatory monocytes, whereas its blockade results in the induction of immunoregulatory APCs and suppression of EAE. We will test this hypothesis in the following specific aims: 1) To determine the impact of GM-CSF on phenotype of APCs and T cells in EAE. We will test the hypothesis that blockade of GM-CSF signaling in monocytes leads to the development of immunoregulatory APCs that promote development of Tr1/Treg cells, resulting in suppression of EAE. 2) To investigate the effect of GM-CSF on the phenotype of microglia/macrophages in chronic phase of EAE. We will test our hypothesis that GM-CSF promotes activation and pro-inflammatory M1 phenotype of macrophages/microglia in chronic phase of EAE, which contributes to disease chronicity. 3) To determine the effects of blocking GM-CSF on phenotype and function of human monocytes. We will test the hypothesis that GM-CSF promotes development of a proinflammatory phenotype of human monocytes. These studies should fill the gap in our knowledge on mechanisms of proinflammatory action of GM- CSF and its relevant cellular targets in EAE/MS, with potential therapeutic effect in certain autoimmune diseases.

粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种促炎因子， 实验性自身免疫性疾病发生和发展所必需的细胞因子 脑脊髓炎（EAE），多发性硬化症（MS）的动物模型。虽然GM-CSF GM-CSF受体（GM-CSFR）主要由致病性Th 17和Th 1细胞产生， 在T和B细胞上表达，但在抗原呈递细胞（APC）上表达。其中， Ly 6ChiCCR 2+单核细胞对于GM-CSF在EAE中的致病作用是必需的。此外，GM- 外周而非CNS细胞中的CSF信号传导在急性脑梗死的发展中起着至关重要的作用。 EAE。然而，缺乏GM-CSF信号转导是否会导致免疫调节的发展， APC尚未被研究，并且CNS细胞中GM-CSF信号传导在EAE慢性化中的作用， 其中小胶质细胞活化起主要作用，仍然未知。 我们的初步结果首次表明， IL-10和Foxp 3表达增加的小鼠的CD 4 + T细胞中， GM-CSF类似地，中和人单核细胞培养物中的GM-CSF导致人单核细胞中GM-CSF的增加。 IL-27和TGF-β产生。基于这些观察，我们假设GM-CSF 诱导促炎性单核细胞，而其阻断导致 免疫调节APC和EAE抑制。我们将在下面测试这个假设 具体目的：1）确定GM-CSF对APCs和T细胞表型的影响， EAE。我们将检验这样的假设，即在单核细胞中阻断GM-CSF信号传导导致 促进Tr 1/Treg细胞发育的免疫调节APC的发育， 抑制EAE。2)目的探讨GM-CSF对白血病细胞表型的影响， 在EAE的慢性期中的小胶质细胞/巨噬细胞。我们将检验我们的假设， 促进慢性炎症中巨噬细胞/小胶质细胞的活化和促炎M1表型 EAE阶段，这有助于疾病慢性化。3)要确定阻塞的影响， GM-CSF对人单核细胞表型和功能的影响我们将检验这个假设， GM-CSF促进人单核细胞的促炎表型的发展。这些 这些研究应该填补我们对GM促炎作用机制的认识上的差距， CSF及其相关细胞靶点在EAE/MS中的作用，在某些疾病中具有潜在的治疗作用。 自身免疫性疾病

项目成果

Chloroquine-treated dendritic cells require STAT1 signaling for their tolerogenic activity.

氯喹处理的树突状细胞需要STAT1信号传导其耐受性活性。

• DOI: 10.1002/eji.201747362
• 发表时间: 2018-07
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Thome R;Bonfanti AP;Rasouli J;Mari ER;Zhang GX;Rostami A;Verinaud L
• 通讯作者: Verinaud L

IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production.

IL-9 通过抑制 GM-CSF 产生来控制中枢神经系统自身免疫。

• DOI: 10.4049/jimmunol.1801113
• 发表时间: 2020
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Yoshimura,Satoshi;Thome,Rodolfo;Konno,Shingo;Mari,ElisabethR;Rasouli,Javad;Hwang,Daniel;Boehm,Alexandra;Li,Yanhua;Zhang,Guang-Xian;Ciric,Bogoljub;Rostami,Abdolmohamad
• 通讯作者: Rostami,Abdolmohamad

Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice.

• DOI: 10.1126/scitranslmed.aba0599
• 发表时间: 2020-11-04
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Casella G;Rasouli J;Boehm A;Zhang W;Xiao D;Ishikawa LLW;Thome R;Li X;Hwang D;Porazzi P;Molugu S;Tang HY;Zhang GX;Ciric B;Rostami A
• 通讯作者: Rostami A

Elevated expression of granulocyte-macrophage colony-stimulating factor receptor in multiple sclerosis lesions.

• DOI: 10.1016/j.jneuroim.2017.12.017
• 发表时间: 2018-04-15
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Imitola J;Rasouli J;Watanabe F;Mahajan K;Sharan AD;Ciric B;Zhang GX;Rostami A
• 通讯作者: Rostami A

Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells.

• DOI: 10.3389/fimmu.2017.01392
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Thomé R;Moore JN;Mari ER;Rasouli J;Hwang D;Yoshimura S;Ciric B;Zhang GX;Rostami AM
• 通讯作者: Rostami AM