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.

粒细胞巨噬细胞刺激因子（GM-CSF）是一种促炎性 细胞因子对于实验自身免疫的发展和进展至关重要 脑脊髓炎（EAE），一种多发性硬化症的动物模型（MS）。虽然GM-CSF是 GM-CSF受体（GM-CSFR）主要由致病性Th17和Th1细胞产生，不是 在T和B细胞上表达，但在抗原呈递细胞（APC）上表示。他们之中， LY6CHICCR2+单核细胞对于GM-CSF在EAE中的致病作用至关重要。此外，GM- 外围的CSF信号传导，而不是CNS细胞，在急性发展中起着至关重要的作用 伊。但是，缺乏GM-CSF信号传导是否导致免疫调节的发展 APC尚未研究，GM-CSF信号在CNS细胞中的作用在EAE慢性中， 小胶质细胞活化起主要作用，仍然未知。 我们第一次的初步结果显示免疫调节的产生增强 APC中的分子，以及缺乏小鼠CD4+ T细胞中IL-10和FOXP3表达增加 GM-CSF。同样，在人单核细胞培养中中和GM-CSF导致增加 IL-27和TGF-β产生。基于这些观察结果，我们假设GM-CSF 诱导促炎单核细胞，而其封锁导致诱导 免疫调节APC和EAE的抑制。我们将在以下来检验这一假设 具体目的：1）确定GM-CSF对APC和T细胞表型的影响 伊。我们将检验以下假设：单核细胞中GM-CSF信号的阻断导致 开发促进TR1/Treg细胞发展的免疫调节APC，导致 在镇压EAE中。 2）研究GM-CSF对表型的影响 EAE慢性期的小胶质细胞/巨噬细胞。我们将测试GM-CSF的假设 促进慢性巨噬细胞/小胶质细胞的激活和促炎的M1表型 EAE的阶段，导致疾病慢性。 3）确定阻塞的影响 GM-CSF关于人类单核细胞的表型和功能。我们将检验以下假设 GM-CSF促进了人类单核细胞的促炎表型的发展。这些 研究应填补我们对GM-促炎作用机制的了解的空白。 CSF及其在EAE/MS中的相关细胞靶标具有某些潜在的治疗作用 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