Innate Immune Activation and Endothelial Cell Dysfunction in Acute Kawasaki Disease

急性川崎病的先天免疫激活和内皮细胞功能障碍

• 批准号: 10311990
• 负责人: JANE C BURNS
• 金额: $ 72.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311990
• 关键词: Acute; Address; Aftercare; Agonist; Aneurysm; Attenuated; Binding; Biology; Blood Vessels; Cardiovascular system; Cell Wall; Cell model; Cell physiology; Child; Childhood; Clinical; Clinical Trials; Combined Modality Therapy; Coronary; Coronary artery; Cultured Cells; Development; Down-Regulation; Endothelial Cells; Endothelium; Enrollment; Etiology; FHA Domain; Functional disorder; GKLF protein; Heart Diseases; Homeostasis; Human; Immune response; Immunology; Impairment; In Vitro; Infant; Inflammasome; Inflammatory; Innate Immune Response; Innate Immune System; Interleukin Activation; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukins; Intravenous Immunoglobulins; Knock-out; Lactobacillus casei; Lead; Leucine-Rich Repeat; Life; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Mesenchymal; MicroRNAs; Molecular; Monoclonal Antibodies; Mucocutaneous Lymph Node Syndrome; Mus; Myocardial Infarction; Myocardial Ischemia; Natural Immunity; Nucleotides; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Patients; Pharmacology; Pilot Projects; Production; Proteins; RNA; Recombinant Interleukins; Recombinants; Research; Role; Signal Transduction; Small Interfering RNA; TNF Receptor-Associated Factors; TNF gene; Testing; Therapeutic; Time; Transcript; Translating; Vascular Diseases; Vascular Endothelial Cell; Vasculitis; Whole Blood; Work; anakinra; antagonist; atorvastatin; base; calcification; cell injury; connective tissue growth factor; coronary lesion; cytokine; data modeling; experimental study; immune activation; improved; in vitro Model; in vitro testing; in vivo; infliximab; inhibitor; knock-down; loss of function; marenostrin; mouse model; novel; novel therapeutic intervention; overexpression; pleiotropism; prevent; restoration; therapy design; treatment effect; vascular inflammation; vascular injury

More than 25% of children with Kawasaki disease (KD), the most common cause of pediatric acquired heart disease, develop coronary artery abnormalities (CAAs) despite standard therapy with intravenous immunoglobulin. Once aneurysms have formed, the damage to the arterial wall is irreversible, such as stenoses and calcification that may lead to ischemic complications. This collaborative team has established that activation of the IL-1 pathway and endothelial-to-mesenchymal transition (EndoMT) with downregulation of krüppel-like factor 4 (KLF4) are key to the pathogenesis of KD vasculitis. Our novel discovery of the central role of TIFA (TNF receptor-associated factor-interacting protein with a forkhead-associated domain) in NLRP3 inflammasome activation in endothelial cell (EC) injury is proposed as a further mechanism of KD vasculitis. We propose a bold plan to unite this research team with expertise in vascular biology, immunology, and clinical KD to unravel the mechanisms underlying vascular injury in KD and pilot a novel therapeutic approach. The guiding hypothesis is that acute KD not only activates the IL-1/TIFA/NLRP3 inflammasome in the endothelium, but also reduces EC homeostasis, both of which are critical in the pathogenesis of KD. The blockade of the IL-1-dependent innate immune response by anakinra (recombinant IL-1R antagonist) in combination with the restoration of EC function by atorvastatin will reduce vascular damage in acute KD. Three specific aims are proposed to test this hypothesis. Specific Aim 1 will delineate the molecular basis by which anakinra blocks activation of the innate immune response associated with KD vasculitis. In vitro, ex vivo, and in vivo experiments will investigate the role of IL-1, TIFA, and NLRP3 in KD-mediated EC dysfunction and vasculitis using pathway-specific siRNA knockdown, recombinant overexpression, pharmacologic agonists and inhibitors (including anakinra), as well as loss-of- function mice. Specific Aim 2 will elucidate the molecular basis by which atorvastatin restores EC function in acute KD. Mouse lines with gain- and loss-of-function of KLF4 as well as lineage tracing experiments will be performed to decipher the molecular mechanisms underlying EC dysfunction in KD vasculopathy. Specific Aim 3 will determine the synergistic effect of anakinra/atorvastatin combination therapy in LCWE-injected mice and in KD patients. LCWE mouse models, including Tifa-/- and Klf4-/-, will be utilized to test the effect of anakinra/atorvastatin combination therapy on vascular inflammation and EC function. Furthermore, acute KD patients with early CAAs will be enrolled in a pilot study of anakinra/atorvastatin combination therapy. Cytokine levels and MMP activity in sera and transcript abundance in whole blood RNA will be measured pre- and post- treatment. These sera will also be tested in vitro with cultured ECs with read-outs for EC innate immune responses and EC dysfunction. The synergistic expertise of the three teams in this multi-PI proposal provides a unique opportunity to understand molecular mechanisms underlying KD vasculopathy and rapidly translate the findings into a pilot study in children with in vitro and in vivo assessments of the treatment effect.

超过25％ 疾病，发展冠状动脉异常（CAAS）任务标准治疗与静脉注射 免疫球蛋白。一旦形成大动脉瘤，对动脉壁的损害是不可逆的，例如stenose 和可能导致缺血并发症的计算。这个协作团队已经确定了激活 IL-1途径和内皮到间质转变（endomt）的下调 因子4（KLF4）是KD血管炎发病机理的关键。我们对TIFA（TNF）中心作用的新颖发现 NLRP3炎症体中与受体相关因子相互作用蛋白与叉头相关结构域） 内皮细胞（EC）损伤的激活是作为KD血管炎的进一步机制。我们提出了一个大胆的 计划将该研究团队与血管生物学，免疫学和临床KD方面的专业知识团结起来，以解开 KD中的血管损伤的机制和一种新型的治疗方法。指导假设 是急性KD不仅激活内皮中的IL-1/TIFA/NLRP3炎症体，而且还会减少EC 稳态，这在KD的发病机理中至关重要。 IL-1依赖性先天的封锁 Anakinra（重组IL-1R拮抗剂）的免疫反应与EC功能的恢复结合 通过阿托伐他汀将减少急性KD中的血管损伤。提出了三个特定目标来检验这一假设。 特定的目标1将描述Anakinra阻止先天免疫激活的分子基础 与KD血管炎有关的反应。体外，体内和体内实验将研究IL-1的作用 TIFA和NLRP3在KD介导的EC功能障碍和使用途径特异性siRNA敲低的血管炎中， 重组过表达，药物激动剂和抑制剂（包括Anakinra），以及丧失 功能小鼠。特定的目标2将阐明代理vastin恢复EC功能的分子基础 急性KD。 KLF4的功能和功能丧失以及谱系跟踪实验的鼠标线将是 进行的是破译KD VasculoPathy中EC功能障碍的分子机制。具体目标 3将确定Anakinra/Atorvastatin联合疗法在LCWE注射小鼠和 在KD患者中。 LCWE鼠标模型（包括TIFA - / - 和KLF4 - / - ）将用于测试 Anakinra/Atorvastatin联合疗法在血管注射和EC功能方面。此外，急性KD 早期CAA的患者将参加Anakinra/Atorvastatin联合疗法的试点研究。细胞因子 将在血清中和全血RNA中的血清中的水平和MMP活性进行测量 治疗。这些血清还将在体外与具有培养的EC进行体外测试 反应和EC功能障碍。该多PI提案中三支团队的协同专业知识提供了一个 理解KD血管病的分子机制的独特机会，并迅速翻译 对接受治疗效果的体外和体内评估儿童进行试验研究的结果。

项目成果

Characterization of SARS-CoV-2 and common cold coronavirus-specific T-cell responses in MIS-C and Kawasaki disease children.

• DOI: 10.1002/eji.202149556
• 发表时间: 2022-01
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Hsieh LE;Grifoni A;Sidney J;Shimizu C;Shike H;Ramchandar N;Moreno E;Tremoulet AH;Burns JC;Franco A
• 通讯作者: Franco A

A machine-learning algorithm for diagnosis of multisystem inflammatory syndrome in children and Kawasaki disease in the USA: a retrospective model development and validation study.

• DOI: 10.1016/s2589-7500(22)00149-2
• 发表时间: 2022-10
• 期刊: LANCET DIGITAL HEALTH
• 影响因子: 30.8
• 作者: Lam, Jonathan Y.;Shimizu, Chisato;Tremoulet, Adriana H.;Bainto, Emelia;Roberts, Samantha C.;Sivilay, Nipha;Gardiner, Michael A.;Kanegaye, John T.;Hogan, Alexander H.;Salazar, Juan C.;Mohandas, Sindhu;Szmuszkovicz, Jacqueline R.;Mahanta, Simran;Dionne, Audrey;Newburger, Jane W.;Ansusinha, Emily;DeBiasi, Roberta L.;Hao, Shiying;Ling, Xuefeng B.;Cohen, Harvey J.;Nemati, Shamim;Burns, Jane C.
• 通讯作者: Burns, Jane C.

Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles.

• DOI: 10.3390/ijms22115655
• 发表时间: 2021-05-26
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Jackson H;Menikou S;Hamilton S;McArdle A;Shimizu C;Galassini R;Huang H;Kim J;Tremoulet A;Thorne A;Fischer R;de Jonge MI;Kuijpers T;Wright V;Burns JC;Casals-Pascual C;Herberg J;Levin M;Kaforou M;On Behalf Of The Perform Consortium
• 通讯作者: On Behalf Of The Perform Consortium

Role of endothelial cells in pulmonary fibrosis via SREBP2 activation.

• DOI: 10.1172/jci.insight.125635
• 发表时间: 2021-11-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Martin M;Zhang J;Miao Y;He M;Kang J;Huang HY;Chou CH;Huang TS;Hong HC;Su SH;Wong SS;Harper RL;Wang L;Bhattacharjee R;Huang HD;Chen ZB;Malhotra A;Rabinovitch M;Hagood JS;Shyy JY
• 通讯作者: Shyy JY

Interleukin-18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis.

• DOI: 10.1002/hep.32776
• 发表时间: 2023-06-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Knorr, Jana;Kaufmann, Benedikt;Inzaugarat, Maria Eugenia;Holtman, Theresa Maria;Geisler, Lukas;Hundertmark, Jana L.;Kohlhepp, Marlene Sophia;Boosheri, Laela M.;Chilin-Fuentes, Daisy R.;Birmingham, Amanda;Fisch, Kathleen M.;Schilling, Joel D.;Loosen, Sven H.;Trautwein, Christian;Roderburg, Christoph;Demir, Milnevver;Tacke, Frank;Hoffman, Hal M.;Feldstein, Ariel E.;Wree, Alexander
• 通讯作者: Wree, Alexander