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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.

项目概要/摘要动脉粥样硬化是大动脉的一种慢性炎症性疾病，也是导致人类死亡的主要原因西方人口。各种免疫介导的机制参与了起始和进展的疾病。细胞因子是炎症的关键介质，也是炎症调节中的新兴参与者动脉粥样硬化。虽然细胞因子的中和已被证明对自身炎症性疾病有效，但靶向细胞因子治疗动脉粥样硬化的疗效仍有待阐明。 IL23是IL6/IL12超家族的细胞因子，由骨髓细胞产生并调节IL17的产生和 IL22 由 T 辅助细胞 IL17 产生 (Th17) 细胞以及 γδ T 细胞和 3 型先天淋巴细胞 (ILC3) 产生在各种炎症模型中。因此，IL23 缺乏会导致 IL17 和 IL22 表达减少并且，在大多数情况下，炎症性疾病的进展会减弱，正如 IBD 所证明的那样，牛皮癣、关节炎和癌症。多项报告表明患者和动物的 IL23 水平升高与动脉粥样硬化有关，指出 IL23 可能具有促炎、促动脉粥样硬化作用。此外，还有几个研究表明 IL17A（一种受 IL23 调节的关键细胞因子）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 的产生而促进动脉粥样硬化由 CD4 Th17 细胞。然而，我们的初步数据揭示了 IL23 在遗传小鼠模型中具有意想不到的动脉粥样硬化作用动脉粥样硬化。在这里，我们建议研究 IL23 抑制动脉粥样硬化的机制发展。根据我们的初步研究结果，我们假设 IL23-IL23R 信号调节动脉粥样硬化中的炎症环境至少通过两种机制来调节：（1）直接抑制来自主动脉骨髓细胞的促炎分子骨桥蛋白（OPN），以及（2）间接地，通过控制肠道中的 IL22 并限制肠道促炎细菌种类的菌群失调微生物群。为了研究 IL23 动脉粥样硬化保护作用的分子和细胞机制，我们将使用良好的建立动脉粥样硬化模型（Ldlr-/- 小鼠），并结合 IL23R 条件性失活（IL23R“floxed”）小鼠）及其潜在下游靶点 OPN 和 IL22（OPN 基因敲除小鼠和 IL22R 条件小鼠）。我们还将使用尖端的分子生物学和组织学技术，以及进行全面的在缺乏保护性 IL23 信号传导的情况下，分析肠道微生物群作为动脉粥样硬化的潜在驱动因素。总体而言，拟议的研究将揭示 IL23 信号传导在动脉粥样硬化中的作用。这部作品具有很强的转化潜力，因为它将揭示无法解释的主要不良心血管事件（MACE） IL23 抑制剂的临床试验中发现。