Does microglial TNFR2 contribute to the protective role of membrane TNF in EAE?

小胶质细胞 TNFR2 是否有助于膜 TNF 在 EAE 中的保护作用？

• 批准号: 8702441
• 负责人: ROBERTA BRAMBILLA
• 金额: $ 22.62万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702441
• 关键词: Ablation; Address; Adverse effects; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Astrocytes; Autoimmunity; Binding; Bone Marrow; Cell Survival; Cell physiology; Cells; Cerebrospinal Fluid; Chimera organism; Chronic; Clinical Trials; Development; Disease; Dominant-Negative Mutation; Equilibrium; Event; Experimental Autoimmune Encephalomyelitis; FDA approved; Functional disorder; Genetic; Goals; Immunity; Individual; Infection; Inflammation; Inflammatory; Infusion procedures; Investigation; Knowledge; Laboratories; Lesion; Light; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Microglia; Modeling; Multiple Sclerosis; Mus; Myelin; Myelogenous; Neurons; Oligodendroglia; One-Step dentin bonding system; Paralysed; Pathologic Processes; Pathology; Patients; Physiological Processes; Play; Population; Production; Quality of life; Receptor Activation; Receptors, Tumor Necrosis Factor, Type II; Recovery; Regulation; Research; Resolution; Rheumatoid Arthritis; Role; Serum; Signal Transduction; TNF gene; Testing; Translations; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States; Work; base; cytokine; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; macrophage; mouse model; myelination; nervous system disorder; neuroprotection; novel; novel therapeutic intervention; oligodendrocyte precursor; pre-clinical; protective effect; public health relevance; receptor; remyelination; repaired; research clinical testing; research study; tool; young adult

DESCRIPTION (provided by applicant): Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in the regulation of numerous physiological and pathological processes such as inflammation, cancer, autoimmunity and infection. TNF is also linked to the development of various neurological disorders, including multiple sclerosis (MS). TNF exists in two biologically active forms, transmembrane (tmTNF) and soluble (solTNF), whose functions are mediated by TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). By virtue of their different binding affinities, solTNF is the primary signaling partner of TNFR1, while tmTNF preferentially signals through TNFR2. The cellular processes activated by the two receptors are often opposite: TNFR1 mediates apoptosis and chronic inflammation, TNFR2 mediates cell survival, resolution of inflammation, immunity and myelination. Numerous studies have underscored the importance of distinguishing between the functions of solTNF and tmTNF, and have associated MS and its animal model experimental autoimmune encephalomyelitis (EAE) to the detrimental effects of solTNF and TNFR1. In our own studies we have demonstrated not only that solTNF is detrimental, but that tmTNF is protective and important for repair and remyelination in EAE. We showed that mice treated with the biologic XPro1595, a dominant negative TNF that selectively blocks solTNF without affecting tmTNF, recover from EAE-induced paralysis. This is associated with neuroprotection, improved myelin integrity and increased remyelination. How does this occur? Our HYPOTHESIS is that selective inhibition of solTNF causes a shift in the balance of TNF receptor activation towards TNFR2. This leads to the downstream activation of TNFR2-dependent cascades which carry out the protective functions of tmTNF in EAE. Since in the CNS TNFR2 is expressed in oligodendrocytes, oligodendrocyte precursors, astrocytes and microglia, all these cell populations could potentially be the effectors of tmTNF beneficial effect. In this proposal we will focus exclusively on microglia. We have found that TNFR2 is expressed in microglia, both in mouse EAE and in MS. Activation of TNFR2 in microglia has been shown to induce the production of anti-inflammatory and neuroprotective mediators. On this basis, we hypothesize that activation of TNFR2 in microglia by tmTNF sets off protective signaling cascades that contribute to tmTNF beneficial effects. The OBJECTIVE of our studies is to determine whether microglial TNFR2 is a mediator of tmTNF protective function in EAE. We will address this question with an innovative genetic approach consisting of a new mouse model generated in our laboratory where TNFR2 is ablated from the myeloid population (LysMcreTNFR2fl/fl mice) to obtain bone-marrow chimeras that will allow for specific investigation of microglial TNFR2. These experiments will shed light on tmTNF-TNFR2 signaling in microglia in vivo, a question that has not been addressed to date. We believe our studies will significantly advance the current knowledge on the role of tmTNF and TNFR2 in EAE, providing the basis for the possible development of a selective solTNF inhibitor as a new therapy for MS.

描述（由申请人提供）：肿瘤坏死因子（TNF）是一种多效性细胞因子，参与调节许多生理和病理过程，如炎症、癌症、自身免疫和感染。TNF还与各种神经系统疾病的发展有关，包括多发性硬化症（MS）。TNF以两种生物活性形式存在，即跨膜（tmTNF）和可溶性（solTNF），其功能由TNF受体1（TNFR 1）和TNF受体2（TNFR 2）介导。由于它们不同的结合亲和力，solTNF是TNFR 1的主要信号传导伴侣，而tmTNF优先通过TNFR 2进行信号传导。由这两种受体激活的细胞过程通常是相反的：TNFR 1介导细胞凋亡和慢性炎症，TNFR 2介导细胞存活、炎症消退、免疫和髓鞘形成。许多研究已经强调了区分solTNF和tmTNF的功能的重要性，并且已经将MS及其动物模型实验性自身免疫性脑脊髓炎（EAE）与solTNF和TNFR 1的有害作用相关联。在我们自己的研究中，我们不仅证明了solTNF是有害的，而且tmTNF对EAE的修复和髓鞘再生具有保护作用和重要性。我们发现，用生物XPro 1595（一种选择性阻断solTNF而不影响tmTNF的显性阴性TNF）治疗的小鼠从EAE诱导的瘫痪中恢复。这与神经保护、改善髓鞘完整性和增加髓鞘再生有关。这是如何发生的？我们的假设是选择性抑制solTNF导致TNF受体活化平衡向TNFR 2转移。这导致TNFR 2依赖性级联的下游激活，其在EAE中执行tmTNF的保护功能。由于在CNS中TNFR 2在少突胶质细胞、少突胶质细胞前体、星形胶质细胞和小胶质细胞中表达，所有这些细胞群都可能是tmTNF有益作用的效应子。在本提案中，我们将专门关注小胶质细胞。我们已经发现TNFR 2在小胶质细胞中表达，在小鼠EAE和MS中。小胶质细胞中TNFR 2的活化已经显示诱导抗炎和神经保护介质的产生。在此基础上，我们假设，激活TNFR 2在小胶质细胞的tmTNF启动保护性信号级联反应，有助于tmTNF的有益效果。我们研究的目的是确定小胶质细胞TNFR 2是否是EAE中tmTNF保护功能的介导者。我们将通过一种创新的遗传方法来解决这个问题，该方法由我们实验室中产生的新小鼠模型组成，其中TNFR 2从骨髓群体（LysMcreTNFR 2fl/fl小鼠）中消融以获得骨髓嵌合体，这将允许对小胶质细胞TNFR 2进行特异性研究。这些实验将揭示体内小胶质细胞中的tmTNF-TNFR 2信号传导，这是一个迄今为止尚未解决的问题。我们相信，我们的研究将显著推进目前对tmTNF和TNFR 2在EAE中作用的认识，为可能开发选择性solTNF抑制剂作为MS的新疗法提供基础。