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 实验性自身免疫的发生和进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，尽管 GM-CSF 是。 主要由致病性 Th17 和 Th1 细胞产生，GM-CSF 受体 (GM-CSFR) 不是 在 T 细胞和 B 细胞上表达，但在抗原呈递细胞 (APC) 上表达。 Ly6ChiCCR2+ 单核细胞对于 GM-CSF 在 EAE 中的致病作用至关重要。 外周细胞而非中枢神经系统细胞中的 CSF 信号传导在急性炎症的发生中起着至关重要的作用。 然而，GM-CSF 信号传导的缺乏是否会导致免疫调节的发展？ 尚未研究 APC，以及 EAE 慢性中 CNS 细胞中 GM-CSF 信号传导的作用， 小胶质细胞激活在其中起主要作用仍不清楚。 我们的初步结果首次显示免疫调节剂的产生增强 APC 中的分子，以及缺乏小鼠的 CD4+ T 细胞中 IL-10 和 Foxp3 的表达增加 同样，中和人单核细胞培养物中的 GM-CSF 会导致 GM-CSF 增加。 IL-27 和 TGF-β 的产生基于这些观察，我们捕获了 GM-CSF。 诱导促炎性单核细胞，而其阻断则导致诱导 免疫调节 APC 和 EAE 抑制 我们将在下面检验这一假设。 具体目标： 1) 确定 GM-CSF 对 APC 和 T 细胞表型的影响 我们将测试单核细胞中 GM-CSF 信号传导的阻断会导致 EAE 的假设。 免疫调节 APC 的发育促进 Tr1/Treg 细胞的发育，从而 2) 研究GM-CSF对EAE表型的影响。 我们将检验我们的假设：GM-CSF。 促进慢性病中巨噬细胞/小胶质细胞的激活和促炎 M1 表型 EAE 阶段，这会导致疾病慢性化 3) 确定阻断的效果。 GM-CSF 对人类单核细胞表型和功能的影响 我们将检验以下假设： GM-CSF 促进人类单核细胞促炎表型的发展。 研究应该填补我们关于 GM-促炎作用机制的知识空白 CSF 及其在 EAE/MS 中的相关细胞靶点，在某些方面具有潜在的治疗作用 自身免疫性疾病。

项目成果

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

A serine protease inhibitor induces type 1 regulatory T cells through IFN-γ/STAT1 signaling.

• DOI: 10.1038/s41423-019-0354-6
• 发表时间: 2020-09
• 期刊: Cellular & molecular immunology
• 影响因子: 24.1
• 作者: Safavi F;Thome R;Li Z;Wang L;Rasouli J;Ciric B;Zhang GX;Rostami A
• 通讯作者: Rostami A

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

• 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

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