Novel Functions of S1P in Neuroinflammation

S1P 在神经炎症中的新功能

• 批准号: 8766543
• 负责人: TOMASZ K KORDULA
• 金额: $ 37.38万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766543
• 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; 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 receptor-associated factor 2; Tumor Necrosis Factor-alpha; Ubiquitination; Work; astrogliosis; chemokine; cofactor; combinatorial; cytokine; design; extracellular; genetic approach; 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 κB, 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（由应用程序提供）：白介素1（IL-1）是一种促炎细胞因子，对于人类多发性硬化症（MS）的发育和进展至关重要，小鼠和实验性自身免疫性脑脊髓炎（EAE）至关重要。尽管IL-1通过激活核因子κB诱导许多细胞因子的表达，但对于MS和EAE来说，诱导几种趋化因子（例如Rantes和IP-10）需要激活另一种转录因子干扰素调节因子-1（IRF-1）。值得注意的是，在MS患者的大脑中激活IRF-1，IRF-1敲除小鼠受到EAE的保护，并且EAE受到中枢神经系统（CNS）的IRF-1 Express调节。我们已经表明，IL-1刺激并更新鞘氨醇激酶1（SPHK1），这是两个产生鞘氨醇-1-磷酸（S1P）的同工酶之一，这是一种调节对炎症重要的细胞过程的脂质介质。在MS患者的CSF中，S1P增加了，并诱导星形胶质细胞增多症。 FTY720，一种由SPHK2磷酸化至S1P Mimetic（FTY720-P）的pro-prug，分泌后的五个S1P受体中的四个（S1P2除外）目前正在III期临床试验中，并有效地降低了MS的频率和频率。 FTY720通过在淋巴细胞上下调S1P1来部分减少MS符号，从而阻止其S1P依赖性淋巴结中的出口。然而，fty720也积累了大脑，在大脑中减少了星形胶质细胞增多。然而，它在中枢神经系统中的影响尚不完全理解。我们进行了两个有趣的观察：1）S1P直接与细胞内凋亡2（CIAP2）的细胞抑制剂结合，并刺激IRF-1的CIAP2介导的K63调节泛素化及其激活。 2）与细胞内S1P相反，细胞外S1P抑制了IRF-1的核转运，rantes诱导和通过星形胶质细胞中的S1P2诱导IP-10表达。这就是我们假设“ S1P通过调节IRF-1功能的新型细胞内和细胞外机制调节大脑注射”。该假设对理解星形胶质细胞介导的神经炎症和MS的S1P，FTY720和IRFS作用的机制具有重要意义。我们提出以下具体目标：目标1。分析细胞内S1P作为CIAP2介导的IRF-1泛素化的辅助因子的作用。目标2。确定细胞外S1P影响IRF-1激活的机制。目标3。定义体内IRF-1的S1P调节的作用。该提案将增强对IL-1，S1P及其在星形胶质细胞中接收器之间的复杂相互作用如何调节感染的理解，并可能为设计更有效的MS疗法铺平道路。