IL-35 inhibits gut microbiota-produced uremic toxin-accelerated endothelial cell activation

IL-35 抑制肠道微生物群产生的尿毒症毒素加速内皮细胞活化

基本信息

批准号：
9764871
负责人：
Xiaofeng Yang
金额：
$ 65.93万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764871
关键词：
Accounting Acetylation Acute Adult Affect Anti-inflammatory Apolipoprotein E Atherosclerosis Binding Blood Vessels CASP1 gene CASP4 gene Calcium Cardiovascular Diseases Cardiovascular system Cell Adhesion Molecules Cellular biology Cessation of life Choline Chronic Kidney Failure Data Development Diet Disease Disease model Endothelial Cells Endotoxins FOXP3 gene Fibronectins Functional disorder G-Protein-Coupled Receptors Gene Activation Gene Expression Generations Genes Goals Histones Hour Human Inflammasome Inflammation Integrins Intercellular adhesion molecule 1 Interleukin-10 Interleukins Lead Ligands Lipids Lipopolysaccharides Lysine Lysophosphatidylcholines Mediating Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Morbidity - disease rate Mus Nitric Oxide PTGS2 gene Paper Pathology Pathway interactions Patients Pattern Phenotype Plasma Play Population Production Prostaglandin-Endoperoxide Synthase Protein Tyrosine Kinase Publications Publishing Reactive Oxygen Species Receptor Inhibition Regulatory T-Lymphocyte Reporting Risk Factors Role STAT1 gene STAT3 gene STAT4 gene Signal Transduction Smooth Muscle Myocytes T-Lymphocyte Testing Therapeutic Toll-like receptors Toxin Up-Regulation Vascular Smooth Muscle chemokine cytokine cytokine therapy effective therapy gain of function gut microbiota hypoxia inducible factor 1 insight loss of function monocyte mortality mouse model novel novel strategies novel therapeutics oxidized low density lipoprotein receptor success trimethyloxamine vascular inflammation

项目摘要

IL-35 inhibits gut microbiota-produced uremic toxin-accelerated endothelial cell activation Chronic kidney disease (CKD) affects 15% of the adult population worldwide. CKD promotes cardiovascular morbidity and mortality. Increased endothelial cell (EC) activation/dysfunction and vascular inflammation play a critical role the development of CKD-accelerated cardiovascular disease (CVD), which begins in the early stages of CKD. New therapies are urgently needed to inhibit EC activation/dysfunction accelerated by CKD. EC dysfunction is associated with reduced nitric oxide (NO) production whereas our new JBC paper showed EC activation features include: 1) increased secretion of cytokines and chemokines; 2) upregulation of EC adhesion molecules; 3) upregulation of additional DAMP receptors; and 4) upregulation of T cell co-stimulation/co-inhibition receptors. Novel strategies targeted at reducing EC activation/dysfunction and vascular inflammation may provide effective treatment in the early stages of CKD. Trimethylamine-N-Oxide (TMAO) is a gut microbiota generated, choline-derived metabolite. TMAO is a newly identified as a uremic toxin, which is strongly elevated in CKD and associated with atherosclerotic CVDs. TMAO induces EC dysfunction and increased vascular inflammation via binding to G-protein coupled receptor, thereby activating mitogen‐activated protein kinase and NF‐κB, and increasing circulating cytokines. We and others reported that interleukin-35 (IL-35) is a new and powerful anti-inflammatory cytokine that inhibits various inflammation. Plasma IL-35 levels are increased in CKD patients. Therefore, the central hypothesis of this proposal is that IL-35 suppresses uremic toxin TMAO-induced EC activation/dysfunction and CKD-accelerated vascular inflammation. Therefore, we will examine this hypothesis via following three aims: 1) To determine expression and suppressive function of IL-35/IL-35R subunits in TMAO-induced human aortic ECs (HAECs) and mouse aortic ECs (MRECs) from CKD mice; 2) To determine the molecular mechanisms, by which IL-35 inhibits EC activation via inhibiting mitochondrial reactive oxygen species (mtROS) generation, suppressing caspase-1(casp1) canonical/casp11 non-canonical inflammasome signaling, and inhibiting histone 3 lysine 14 acetylation (H3K14ac) induced EC activation gene expression; and 3) To determine the suppressing roles of two IL-35 subunits (p35, and EBI3) and an IL-35 receptor (IL-35R) subunit (IL12Rβ2) in CKD mouse model. The aim 3 will be explored through the use of a novel IL-35 therapy (gain of function) in CKD mouse model, and four loss of function CKD models including p35-/- CKD mice, EBI-3-/- CKD mice, global IL-12Rβ2-/- CKD mice and EC-specific IL12Rb2-/- CKD mice to determine the suppressive roles of IL-35 signaling in EC dysfunction and vascular inflammation in CKD. The significance of this proposal is that the success of these studies should have a major impact in the field, and provide novel mechanistic insights into IL-35 in suppressing TMAO-induced EC activation and CKD-accelerated vascular inflammation, which could lead to the potential development of novel therapeutics for CKD-accelerated CVDs.

IL-35抑制肠道微生物群产生的尿毒症毒素加速性内皮细胞激活慢性肾脏疾病（CKD）影响全球15％的成年人口。 CKD促进心血管发病率和死亡率。增加内皮细胞（EC）激活/功能障碍血管炎症起着CKD加速的发展起着至关重要的作用心血管疾病（CVD），始于CKD的早期。新疗法是迫切需要抑制CKD加速的EC激活/功能障碍。 EC功能障碍是与一氧化氮（NO）生产减少有关，而我们的新JBC纸激活特征包括：1）细胞因子和趋化因子的分泌增加； 2）上调 EC粘附分子的； 3）上调其他潮湿受体； 4）上调 T细胞共刺激/共抑制接收器。针对减少EC的新型策略激活/功能障碍和血管感染可能会在早期提供有效的治疗方法 CKD的阶段。三甲胺-N-氧化物（TMAO）是肠道菌群产生的，胆碱衍生的代谢物。 TMAO是新近识别的尿毒症毒素，在CKD和与动脉粥样硬化CVD相关。 TMAO影响EC功能障碍并增加血管通过与G蛋白偶联受体结合的炎症，从而激活有丝分裂原激活蛋白激酶和NF-κB，并增加循环细胞因子。我们和其他人报告白介素-35（IL-35）是一种新的且强大的抗炎细胞因子，可抑制各种炎。 CKD患者的血浆IL-35水平升高。因此，中央该提议的假设是IL-35抑制了尿毒症毒素TMAO诱导的EC 激活/功能障碍和CKD加速血管炎症。因此，我们将检查通过以下三个目的这一假设：1）确定表达和抑制功能 TMAO诱导的人主动脉ECS（HAEC）和小鼠主动脉ECS中的IL-35/IL-35R亚基的（MREC）来自CKD小鼠； 2）确定IL-35抑制的分子机制通过抑制线粒体活性氧（MTROS）产生的EC激活，抑制caspase-1（CASP1）规范/casp11非典型炎性体信号传导和抑制组蛋白3赖氨酸14乙酰化（H3K14AC）诱导EC激活基因表达；和 3）确定两个IL-35亚基（P35和EBI3）和IL-35的抑制作用 CKD小鼠模型中的接收器（IL-35R）亚基（IL12Rβ2）。目标3将通过在CKD小鼠模型中使用新型IL-35治疗（功能获得），四个丢失功能CKD模型，包括p35 - / - CKD小鼠，EBI-3 - / - CKD小鼠，全局IL-12Rβ2 - / - CKD 小鼠和EC特异性IL12RB2 - / - CKD小鼠确定IL-35的抑制作用 CKD中EC功能障碍和血管炎症的信号传导。这一点的意义建议是这些研究的成功应该对该领域产生重大影响，并且在抑制TMAO诱导的EC激活和 CKD加速血管感染，这可能导致新型的潜在发展 CKD加速CVD的治疗剂。