Novel Functions of S1P in Neuroinflammation

S1P 在神经炎症中的新功能

• 批准号: 8374101
• 负责人: TOMASZ K KORDULA
• 金额: $ 35.13万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374101
• 关键词: Address; Affect; Agonist; Antiviral Response; Astrocytes; Binding; Brain; CXCL10 gene; Cell physiology; Cells; Development; Disease; Encephalitis; Enzymes; Event; Experimental Autoimmune Encephalomyelitis; Frequencies; Genetic; Human; IRF1 gene; Inflammation; Inflammatory; Inflammatory Response; Interferon Regulatory Factor 1; Interleukin-1; Isoenzymes; Knock-out; Knockout Mice; Ligase; Lymphocyte; Mediating; Molecular; Multiple Sclerosis; Mus; Neuraxis; Nuclear; Nuclear Translocation; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Process; Prodrugs; RANTES; Receptor Signaling; Regulation; Role; SPHK1 enzyme; Severities; Signal Transduction; Sphingosine-1-Phosphate Receptor; Symptoms; TNF gene; TNF receptor-associated factor 2; Ubiquitination; Work; astrogliosis; chemokine; cofactor; combinatorial; cytokine; design; extracellular; human BIRC3 protein; in vivo; lipid mediator; lymph nodes; mimetics; neuroinflammation; novel; prevent; receptor; receptor coupling; sphingosine 1-phosphate; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Interleukin 1 (IL-1) is a proinflammatory cytokine that is critical for the development and progression of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. Although IL-1 induces expression of many cytokines via the activation of nuclear factor ?B, induction of several chemokines important for MS and EAE, such as RANTES and IP-10, requires the activation of an additional transcription factor, interferon regulatory factor-1 (IRF-1). Significantly, IRF-1 is activated in the brains of MS patients, IRF-1 knockout mice are protected from EAE, and EAE is regulated by IRF-1 expressed in the central nervous system (CNS). We have shown that IL-1 stimulates and upregulates sphingosine kinase 1 (SphK1), one of the two isoenzymes that generate sphingosine-1-phosphate (S1P), a lipid mediator that regulates diverse cellular processes important for inflammation. S1P is increased in the CSF of MS patients and induces astrogliosis. FTY720, a pro-drug that is phosphorylated by SphK2 to an S1P mimetic (FTY720-P) and after secretion targets four of the five S1P receptors, except S1P2, is currently in phase III clinical trials, and effectively reduces the frequency and severity of MS. FTY720 reduces MS symptoms, in part, by downregulating S1P1 on lymphocytes thus preventing their S1P-dependent egress from the lymph nodes. However, FTY720 also accumulates in the brain where it reduces astrogliosis; nevertheless, its effects in the CNS are incompletely understood. We made two intriguing observations: 1) S1P directly binds to cellular inhibitor of apoptosis 2 (cIAP2) inside cells and stimulates cIAP2-mediated K63 regulatory ubiquitination of IRF-1 and its activation. 2) In contrast to intracellular S1P, extracellular S1P suppresses nuclear translocation of IRF-1 and induction of RANTES and IP-10 expression via S1P2 in astrocytes. Thus, we hypothesize that "S1P modulates brain inflammation by novel intracellular and extracellular mechanisms that regulate IRF-1 functions". This hypothesis has significant implications for understanding mechanisms of S1P, FTY720, and IRFs actions in astrocyte-mediated neuroinflammation and MS. We propose the following specific aims: Aim 1. Analyze the role of intracellular S1P as a cofactor for cIAP2-mediated ubiquitination of IRF-1. Aim 2. Identify the mechanisms by which extracellular S1P affects IRF-1 activation. Aim 3. Define the roles of S1P regulation of IRF-1 in vivo. This proposal will enhance understanding of how the intricate interplay between IL-1, S1P and its receptors in astrocytes regulates inflammation and could pave the way for the design of even more effective MS therapies.

描述(申请人提供)：白介素1(IL-1)是一种促炎细胞因子，对人类多发性硬化症(MS)和小鼠实验性自身免疫性脑脊髓炎(EAE)的发生和发展至关重要。尽管IL-1通过核因子β的激活诱导多种细胞因子的表达，但一些对MS和EAE重要的趋化因子的诱导，如RANTES和IP-10，需要另一个转录因子-干扰素调节因子-1(IRF-1)的激活。值得注意的是，IRF-1在MS患者的大脑中被激活，IRF-1基因敲除的小鼠受到EAE的保护，EAE受到中枢神经系统(CNS)表达的IRF-1的调节。我们已经证明，IL-1刺激和上调鞘氨醇激酶1(SphK1)，SphK1是产生鞘氨醇-1-磷酸(S1P)的两种同工酶之一，S1P是一种脂质介质，调节着对炎症至关重要的各种细胞过程。MS患者脑脊液中S1P水平升高，并诱导星形胶质细胞增生。FTY720是一种前体药物，被SphK2磷酸化成S1P模拟物(FTY720-P)，在分泌后靶向五个S1P受体中的四个，除S1P2外，目前处于第三阶段临床试验，有效地降低了MS的频率和严重程度，FTY720通过下调淋巴细胞上的S1P1，从而防止它们依赖S1P离开淋巴结来缓解MS症状。然而，FTY720也积聚在大脑中，在那里它可以减少星形胶质细胞增生；然而，它在中枢神经系统的作用还不完全清楚。我们做了两个有趣的观察：1)S1P直接与细胞内的细胞凋亡抑制因子2(CIAP2)结合，并刺激cIAP2介导的K63调节IRF-1的泛素化和激活。2)与细胞内S1P相反，细胞外S1P通过S1P2抑制星形胶质细胞IRF-1的核转位以及RANTES和IP-10的表达。因此，我们假设“S1P通过调节IRF-1功能的新的细胞内和细胞外机制来调节脑部炎症”。这一假说对于理解S1P、FTY720和IRFs在星形胶质细胞介导的神经炎症和MS中的作用机制具有重要意义。我们提出了以下具体目标：目的1.分析细胞内S1P作为辅助因子在cIAP2介导的IRF-1泛素化中的作用。目的2.明确细胞外S1P影响IRF-1激活的机制。目的3.明确IRF-1的S1P调控在体内的作用。这项提议将加强对IL-1、S1P及其星形胶质细胞受体之间复杂的相互作用如何调节炎症的理解，并可能为设计更有效的多发性硬化症疗法铺平道路。