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The unexpected role of IL-23 cytokine in atherosclerosis

IL-23细胞因子在动脉粥样硬化中的意想不到的作用

基本信息

批准号：
10268140
负责人：
Ekaterina Koltsova
金额：
$ 46.28万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268140
关键词：
16S ribosomal RNA sequencing Acceleration Address Adhesiveness Anabolism Animals Antibodies Aorta Arteries Arthritis Atherosclerosis Bacteria Cardiovascular system Cause of Death Cells Clinical Trials Coupled Data Developed Countries Development Disease Disease Progression Event Genetic Healthcare Histological Techniques Homeostasis IL17 gene IL6 gene ITGAM gene ITGAX gene Immune Immunotherapeutic agent In Vitro Inflammation Mediators Inflammatory Inflammatory Response Interleukin-12 Interleukin-17 Intestines Knockout Mice Light LoxP-flanked allele Lymphoid Cell Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Molecular Biology Mus Myeloid Cells Myocardial Infarction Nature Pathogenicity Pathway interactions Patients Play Population Predisposing Factor Prevotella Production Property Psoriatic Arthritis Receptor Signaling Regulation Reporting Repression Research Role Sampling Scheme Serum Signal Transduction Stroke Testing Therapeutic Tissues Up-Regulation Work atheroprotective attenuation autoinflammatory base cell type chronic inflammatory disease cytokine dysbiosis fecal microbiota glycosylation gut microbiota hypercholesterolemia immune activation immunoregulation in vivo inhibitor/antagonist interleukin-23 macrophage microbial microbiota mouse model neutralizing antibody novel novel therapeutics osteopontin protective effect receptor receptor expression γδ T cells

项目摘要

Project Summary/Abstract Atherosclerosis is a chronic inflammatory disease of the large arteries and a major cause of death among western populations. Various immune-mediated mechanisms are implicated into the initiation and progression of the disease. Cytokines are key mediators of inflammation and emerging players in the regulation of atherosclerosis. While neutralization of cytokines has been proven effective in auto-inflammatory diseases, the therapeutic benefit of targeting cytokines in atherosclerosis remains to be elucidated. IL23, a cytokine of IL6/IL12 superfamily, is produced by myeloid cells and regulates the production of IL17 and IL22 by T helper IL17 producing (Th17) cells and also by γδ T cells, and type 3 innate lymphoid cells (ILC3) in various inflammatory models. As a result, IL23 deficiency leads to the reduction of IL17 and IL22 expression and, in most cases, attenuation of the inflammatory disease progression as it was demonstrated for IBD, psoriasis, arthritis and cancer. Multiple reports demonstrated increased levels of IL23 in patients and animals with atherosclerosis, pointing out to possible pro-inflammatory pro-atherogenic role of IL23. Additionally, several studies have implicated IL17A, a key cytokine regulated by IL23, as important pro-atherogenic mediator. These findings led us to speculate that IL23 would promote atherosclerosis, likely via upregulation of IL17 production by CD4 Th17 cells. Our preliminary data however revealed an unexpected atheroprotective role for IL23 in genetic mouse model of atherosclerosis. Here we propose to investigate the mechanism(s) by which IL23 suppresses atherosclerosis development. Based on our preliminary findings, we hypothesize that IL23-IL23R signaling regulates the inflammatory mileu in atherosclerosis by at least two mechanisms: (1) by directly suppressing expression of the pro-inflammatory molecule osteopontin (OPN) from myeloid cells in the aortas, and (2) indirectly, by controlling IL22 in the intestine and limiting the dysbiotic outgrowth of pro-inflammatory bacterial species of the gut microbiota. To study molecular and cellular mechanisms of atheroprotective action of IL23, we will use a well- established model of atherosclerosis (Ldlr-/- mice) coupled with conditional inactivation of IL23R (IL23R “floxed” mice) and its potential downstream targets OPN and IL22 (OPN knockout mice and IL22R conditional mice). We will also use cutting edge molecular biology and histological techniques, as well as perform comprehensive analysis of intestinal microbiota as a potential driver of atherosclerosis in the absence of protective IL23 signaling. Overall, the proposed research will uncover the role of IL23 signaling in atherosclerosis. This work has strong translational potential because it will shed light on unexplained major adverse cardiovascular events (MACE) seeing in clinical trials with IL23 inhibitors.

项目摘要/摘要动脉粥样硬化是一种大动脉的慢性炎症性疾病，是西方人。多种免疫调节机制参与了肿瘤的发生和发展。这种疾病的危害。细胞因子是炎症的关键介质和调节的新兴参与者动脉硬化。虽然中和细胞因子已被证明对自发性炎症性疾病有效，但靶向细胞因子在动脉粥样硬化中的治疗益处仍有待阐明。 IL-23是IL-6/IL-12超家族的一种细胞因子，由髓系细胞产生，调节IL-17的产生由产生IL 17的辅助性T细胞(Th17)、γδT细胞和3型固有淋巴样细胞(ILC3)产生在各种炎症模型中。因此，IL23缺乏导致IL17和IL22的表达减少而且，在大多数情况下，炎症性疾病的进展被证明是IBD的减缓，牛皮癣、关节炎和癌症。多份报告显示患者和动物体内IL23水平升高对于动脉粥样硬化，指出IL23可能具有促炎、促动脉粥样硬化的作用。此外，还有几个研究表明，IL17A是受IL23调控的关键细胞因子，是重要的促动脉粥样硬化介质。这些研究结果使我们推测，IL23可能通过上调IL17的产生来促进动脉粥样硬化通过CD4Th17细胞。然而，我们的初步数据显示，在遗传小鼠模型中，IL23具有意想不到的动脉粥样硬化保护作用动脉粥样硬化。本研究旨在探讨白介素23抑制动脉粥样硬化的机制(S) 发展。根据我们的初步发现，我们假设IL23-IL23R信号调节动脉粥样硬化中的炎症反应至少有两种机制：(1)直接抑制血管内皮生长因子的表达促炎分子骨桥蛋白(OPN)来自主动脉中的髓系细胞，以及(2)通过控制 IL-22在肠道中的作用，并限制肠道促炎细菌种类的非生物生长微生物区系。为了研究IL23抗动脉粥样硬化作用的分子和细胞机制，我们将使用一种良好的建立动脉粥样硬化模型(LDLR-/-小鼠)并条件失活IL23R(IL23R) OPN和IL22(OPN基因敲除小鼠和IL22R条件性小鼠)。我们还将使用尖端的分子生物学和组织学技术，以及执行全面的在缺乏保护性IL23信号的情况下，肠道微生物区系作为动脉粥样硬化的潜在驱动因素的分析。总体而言，拟议的研究将揭示IL23信号在动脉粥样硬化中的作用。这部作品有很强的翻译潜力，因为它将阐明不明原因的主要不良心血管事件(MACE) 在IL23抑制剂的临床试验中看到。