IL-37: a novel regulator of inflammation in CNS autoimmunity

IL-37：中枢神经系统自身免疫炎症的新型调节剂

• 批准号: 10369694
• 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: 2021
• 资助国家: 美国
• 起止时间: 2021-03-11 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369694
• 关键词: Adult; Amphiregulin; Animal Model; Astrocytes; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Brain; CNS autoimmunity; Cells; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Disease Progression; Experimental Autoimmune Encephalomyelitis; Family; Feedback; Genetic Transcription; Human; Immune; Immune response; Immunomodulators; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-10; Interleukin-12; Interleukins; Knockout Mice; Lead; Literature; Lymphocyte; Microglia; Multiple Sclerosis; Mus; Myeloid Cells; Neurons; Oligodendroglia; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Production; Property; Regulatory T-Lymphocyte; Relapse; Rodent; Role; Serum; Severities; Signal Transduction; Slice; Source; System; Testing; Tissues; Transgenic Mice; Up-Regulation; base; brain tissue; clinical application; conditional knockout; cytokine; effective therapy; experience; immunoregulation; insight; interleukin-23; macrophage; member; monocyte; multiple sclerosis patient; multiple sclerosis treatment; neuroinflammation; novel; receptor; receptor expression; tissue repair; transcription factor

SUMMARY Current “disease-modifying drugs” for MS have changed the course of disease with decrease in relapse and possible slowing of the progression. however, many patients eventually experience relapses and/or disease progression. There is thus a clearly unmet need for developing safer and more effective MS therapies. IL-37, a member of the IL-1 family of cytokines, has been recently recognized as a novel immunoregulatory cytokine. Importantly, IL-37 exerts its function through a “dual-effect” property, i.e., both as a secreted cytokine that will act through its receptor IL-37R (SIGIRR and IL-18Ra) and as a transcription factor, and this distinct property may make IL-37 a more powerful immunomodulator than most conventional cytokines for clinical application. Based on the literature and our preliminary observations, we hypothesize that IL-37 is a key regulator of inflammation in CNS autoimmunity through induction of amphiregulin, a tissue-repair associated cytokine with immunomodulatory properties. To test this hypothesis, we propose the following specific aims: (1) To define IL-37R expression and IL-37 responsiveness in immune cells of MS patients. We will first identify the source(s) of IL-37 and compare IL-37R expression and responsiveness to IL-37 in immune cells of MS patients vs. healthy controls. We will also test our hypothesis that IL-37 treatment will block proinflammatory monocyte- or Th1/Th17 cell-induced demyelination, using a novel organotypic slice culture system of adult human brain tissue. (2) To determine the effect of IL-37 on CNS resident cells during autoimmune neuroinflammation. We will first test the effect of IL-37 on microglia, astrocytes and oligodendrocytes of murine and human origin. We will then determine the expression of IL-37R in CNS resident cells from patients with MS. Finally, we will test if upregulation of the IL-37R (TIR8 subunit) suppresses neuroinflammation. 3) To investigate the induction of the amphiregulin pathway as a possible mechanism of IL-37 action. This will be tested in amphiregulin conditional knockout EAE mice and monocytes and T/B cells of healthy subjects and. MS patients. Information gained from these studies could result in a better understanding of pathogenic mechanisms of MS and in the development of new strategies for regulating the immune response in order to stop the progression of this disease, and likely other autoimmune diseases.

总结 目前用于MS的“疾病修饰药物”已经改变了疾病的进程， 复发和可能减缓进展。然而，许多患者最终经历 复发和/或疾病进展。因此，开发更安全、更安全的 更有效的MS疗法IL-37是细胞因子IL-1家族的一员，最近已被证实是IL-1家族的一员。 被认为是一种新型免疫调节细胞因子。重要的是，IL-37通过一种免疫调节剂发挥其功能。 “双效”性质，即，作为分泌的细胞因子，其将通过其受体IL-37 R（SIGIRR）起作用 和IL-18 Ra）和作为转录因子，并且这种独特的性质可能使IL-37更强大， 比大多数常规细胞因子更适合于临床应用。基于文献和 根据我们的初步观察，我们假设IL-37是CNS炎症的关键调节因子， 通过诱导双调蛋白（一种组织修复相关细胞因子， 免疫调节特性。为了验证这一假设，我们提出了以下具体目标：（1） 定义MS患者免疫细胞中IL-37 R表达和IL-37应答性。我们将首先 确定IL-37的来源，并比较免疫细胞中IL-37 R的表达和对IL-37的反应性。 MS患者与健康对照的细胞。我们还将检验我们的假设，即IL-37治疗将阻断 促炎性单核细胞或Th 1/Th 17细胞诱导的脱髓鞘，使用新的器官型切片 成人脑组织培养体系。(2)确定IL-37对CNS驻留细胞的作用 自身免疫性神经炎症我们将首先测试IL-37对小胶质细胞、星形胶质细胞和胶质细胞的作用。 鼠和人来源的少突胶质细胞。然后我们将确定IL-37 R在CNS中的表达， 最后，我们将测试IL-37 R（TIR 8亚基）的上调是否与MS患者的驻留细胞有关。 抑制神经炎症3)为了研究双调蛋白途径作为一种 IL-37作用的可能机制。这将在双调蛋白条件性敲除EAE小鼠中进行测试 以及健康受试者的单核细胞和T/B细胞。MS患者 从这些研究中获得的信息可以更好地了解致病性 MS的机制，并在发展新的战略，调节免疫反应， 以阻止这种疾病的进展，以及可能的其他自身免疫性疾病。