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

基本信息

批准号：
10199564
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-11 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10199564
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 neuroinflammation novel receptor receptor expression tissue repair transcription factor

项目摘要

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.

概括目前治疗多发性硬化症的“疾病缓解药物”已经改变了病程，减少了然而，许多患者最终都会经历复发和可能的进展减慢。因此，对于开发更安全和/或疾病进展的需求显然尚未得到满足。 IL-37 是细胞因子 IL-1 家族的成员，最近已成为更有效的 MS 疗法。重要的是，IL-37 通过一种新型免疫调节细胞因子发挥其功能。 “双效”特性，即既作为分泌细胞因子，又通过其受体 IL-37R (SIGIRR 和 IL-18Ra）并作为转录因子，这种独特的特性可能使 IL-37 成为更强大的根据文献和临床应用，免疫调节剂优于大多数常规细胞因子。我们的初步观察结果表明，IL-37 是中枢神经系统炎症的关键调节因子通过诱导双调蛋白（一种与组织修复相关的细胞因子）来产生自身免疫为了检验这一假设，我们提出以下具体目标：（1）我们首先定义 MS 患者免疫细胞中的 IL-37R 表达和 IL-37 反应性。识别 IL-37 的来源并比较免疫中 IL-37R 的表达和对 IL-37 的反应性我们还将检验我们的假设，即 IL-37 治疗会阻断。使用新型器官切片进行促炎性单核细胞或 Th1/Th17 细胞诱导的脱髓鞘 (2) 测定IL-37对CNS驻留细胞的影响在自身免疫性神经炎症期间，我们将首先测试 IL-37 对小胶质细胞、星形胶质细胞和然后我们将测定小鼠和人类来源的少突胶质细胞中 IL-37R 的表达。最后，我们将测试 IL-37R（TIR8 亚基）是否上调。 3) 研究双调蛋白途径的诱导。 IL-37 作用的可能机制将在双调蛋白条件敲除 EAE 小鼠中进行测试。以及健康受试者和 MS 患者的单核细胞和 T/B 细胞。从这些研究中获得的信息可以使人们更好地了解致病菌 MS 的机制以及开发调节免疫反应的新策略以阻止这种疾病以及可能的其他自身免疫性疾病的进展。