Molecular and Cellular Mechanisms of IL-17 Signaling

IL-17 信号传导的分子和细胞机制

• 批准号: 8453438
• 负责人: Xiaoxia Li
• 金额: $ 37.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8453438
• 关键词: Active Immunization; Adoptive Transfer; Antigens; Astrocytes; Attenuated; Autoimmune Diseases; Autoimmune Process; Blood Vessels; Boxing; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Cerebrum; Chronic; Demyelinations; Development; Disease; Endothelial Cells; Endothelium; Event; Experimental Autoimmune Encephalomyelitis; Gene Expression; Gene Targeting; Genes; Goals; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Interleukin-6; Leukocytes; Ligands; Lymphocyte; MAP Kinase Gene; Mediating; Meningeal; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Nerve Degeneration; Neuraxis; Neuroectoderm; Neurologic Deficit; Neurons; Oligodendroglia; Pathogenesis; Pathway interactions; Peptides; Phosphotransferases; Play; Positioning Attribute; Process; Recruitment Activity; Reporting; Role; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Structure of choroid plexus; Subarachnoid Space; T-Lymphocyte; TRAF6 gene; Testing; Therapeutic; Tissues; Ubiquitination; base; cell type; central nervous system demyelinating disorder; chemokine; cytokine; interleukin-23; macrophage; neutrophil; novel; novel therapeutics; public health relevance; receptor; trafficking; transcription factor; ubiquitin-protein ligase; white matter

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is widely used to dissect molecular mechanisms of MS and to develop new therapeutic strategies. Studies of EAE have helped define the sequence of events involved in the development of autoimmune CNS-directed inflammatory diseases, including the initiation stage (activation and expansion of neuroantigen-reactive CD4 T lymphocytes outside of CNS) and effector stage (recruitment and reactivation of neuroantigen-reactive CD4 T lymphocytes and subsequent inflammatory response within CNS). Recent studies have shown that a distinct CD4 T cell lineage -Th17 cells driven by TGF /IL-6/IL-23 play a critical role in the development of EAE. IL-17 produced by Th17 functions as an inflammatory cytokine and plays an important role in the pathogenesis of EAE by upregulating the expression of cytokines and chemokines. EAE is markedly suppressed in mice lacking IL-17 or IL-17 receptor. Studies using IL-17-specific inhibition indicate that IL-17-mediated signaling plays a critical role in the effector stage of EAE. We and others have identified Act1 as an essential IL-17 signaling molecule recruited to IL-17 receptor (IL-17R) upon IL-17 stimulation through SEFIR-SEFIR domain interaction. We recently reported that Act1 is a novel bona fide U-box E3 ubiquitin ligase, whose activity is essential for IL-17-mediated signaling and inflammatory gene expression. While IL-17 plays an essential role in the development of EAE, it remains unclear how IL-17-mediated signaling in different cellular compartments participates in the CNS in EAE. We now show that Th17 cells are robustly generated in Act1-deficient mice and normally infiltrate the Act1-deficient CNS but fail to recruit hematogenously derived lymphocytes, neutrophils, and macrophages into the CNS. Importantly, Act1 deficiency in endothelial cells or in macrophages/microglia did not substantially impact the development of EAE. However, targeted Act1 deficiency in neuroectoderm derived CNS resident cells (including astrocytes, oligodendrocytes and neurons) resulted in significantly reduced EAE severity whether EAE was induced by active immunization or adoptive transfer of myelin-specific Th17 cells. Based on these findings, we hypothesize that IL-17-induced Act1-mediated signaling in different CNS resident cells coordinately mediate leukocyte recruitment, demyelination and neurodegeneration during autoimmune induced inflammation of the CNS. To test this hypothesis, we propose the following Specific Aims: Aim 1: Investigate the cellular mechanism of IL-17 signaling in the Th17-mediated pathogenesis of EAE. Aim 2: Elucidate the molecular mechanism by which Act1 mediates IL-17 signaling and develop decoy (inhibitory) peptides as a new therapeutic strategy for CNS inflammation, demyelination and neurodegeneration.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CNS）的慢性炎症性脱髓鞘疾病。实验性自身免疫性脑脊髓炎（EAE）广泛用于剖析MS的分子机制并制定新的治疗策略。对EAE的研究有助于定义与自身免疫性CNS导向炎症性疾病开发有关的事件的顺序CNS）。最近的研究表明，由TGF /IL-6 /IL-23驱动的独特的CD4 T细胞谱系-TH17细胞在EAE的发展中起着至关重要的作用。 Th17产生的IL-17通过上调细胞因子和趋化因子的表达来充当炎症细胞因子，在EAE的发病机理中起重要作用。在缺乏IL-17或IL-17受体的小鼠中，EAE明显抑制。使用IL-17特异性抑制作用的研究表明，IL-17介导的信号传导在EAE效应阶段起关键作用。我们和其他人通过SEFIR-SEFIR-SEFIR结构域的相互作用将ACT1确定为IL-17受体（IL-17R）的必需IL-17信号分子。我们最近报道说，ACT1是一种新颖的真正的U-box E3泛素连接酶，其活性对于IL-17介导的信号传导和炎症基因表达至关重要。尽管IL-17在EAE的发展中起着至关重要的作用，但尚不清楚不同细胞室中IL-17介导的信号如何参与EAE中的CNS。现在，我们表明Th17细胞在ACT1缺陷型小鼠中有强烈的生成，并通常渗入ACT1缺陷的中枢神经系统，但无法募集血源性衍生的淋巴细胞，中性粒细胞和巨噬细胞。重要的是，内皮细胞或巨噬细胞/小胶质细胞中的ACT1缺乏症不会显着影响EAE的发展。然而，靶向ACT1缺乏神经外科衍生的CNS驻留细胞（包括星形胶质细胞，少突胶质细胞和神经元）导致EAE的严重程度显着降低，无论是通过主动免疫还是通过髓磷脂特异性Th17细胞诱导EAE。基于这些发现，我们假设在不同CNS驻留细胞中IL-17诱导的ACT1介导的信号传导在自身免疫性诱导的CNS炎症过程中协同介导白细胞募集，脱髓鞘和神经变性。为了检验这一假设，我们提出了以下特定目的：目标1：研究EAE的Th17介导的发病机理中IL-17信号的细胞机制。目标2：阐明ACT1介导IL-17信号传导并发展诱饵（抑制）肽的分子机制，作为CNS炎症，脱髓鞘和神经变性的新治疗策略。