Studies of a new checkpoint regulator in controlling lung inflammation

控制肺部炎症的新检查点调节剂的研究

• 批准号: 10229265
• 负责人: Zhiqiang Zhang
• 金额: $ 24.23万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229265
• 关键词: Address; Affect; Air; Allergens; Area; Asthma; Autoimmunity; Binding; Biological Assay; Biological Response Modifiers; Caspase; Cell physiology; Cells; Chronic; Chronic Disease; Clinical; Clinical Trials; Communicable Diseases; DNA Methylation; DNA mapping; Development; Disease; Down-Regulation; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Extrinsic asthma; Family; Family member; Host Defense; Immune; Immune response; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Innate Immune Response; Innate Immune System; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-18; Invaded; Investigation; Knockout Mice; Length; Link; Lung; Lung Inflammation; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Modification; Molecular; Morbidity - disease rate; Mucosal Immune System; Mus; Natural Immunity; Pathway interactions; Phase; Positioning Attribute; Production; Proteins; Pyroglyphidae; Receptor Signaling; Respiratory System; Rhinovirus; Rhinovirus infection; SYK gene; Scaffolding Protein; Services; Signal Transduction; Site; Source; Stimulus; System; Systemic Lupus Erythematosus; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Toll-like receptors; Ubiquitination; Viral; Work; airway obstruction; allergic airway disease; allergic airway inflammation; anakinra; asthma exacerbation; asthma model; asthmatic patient; cell type; chromatin modification; cytokine; histone modification; immunoregulation; in vivo; insight; microorganism; mortality; mouse model; multicatalytic endopeptidase complex; novel; pathogen; protein degradation; receptor; response; scaffold; selective expression; sensor; tool; ubiquitin-protein ligase

Project Summary Allergic airway disease such as allergic asthma is a T lymphocyte-controlled chronic disease caused by inflammation in the respiratory tracts, and usually results from immune responses to inhaled allergens, and key features include epithelial damage, airflow obstruction and bronchial hyperresponsiveness. Accumulating evidence suggests the involvement of inflammasome activation and IL-1 family cytokines including IL-1α, IL-1β, IL-18 and IL-33 in the development of allergic asthma. Additionally, viral lung epithelial cells (LECs) infections, most frequently with rhinovirus, are predominantly associated with asthma exacerbations promoted by epithelial IL-33. LECs are a physical barrier between allergens and the mucosal immune system. Importantly, after activation, LECs become innate immune-like cells to produce robust proinflammatory cytokines. However, the molecular basis of LECs activation and IL-1 family cytokines production in allergic asthma remains elusive. The innate immune cells use sensors and adaptors to recognize pathogens, resulting in production of cytokines against infections. This immune response must be regulated to effectively control and eliminate invading microorganisms while minimizing tissue inflammation. Ubiquitination has emerged as a pivotal mechanism to control this response in the innate immune system. A key component of the ubiquitination system is E3 ligase to specifically recognize the substrate for modification. We recently found that a tripartite interaction motif (TRIM) family member, E3 ligase TRIM68, is selectively expressed in LECs. Our preliminary studies show that TRIM68 regulates both inflammasome activation and production of full-length IL-33 in LECs after HDM extract-treatment or rhinovirus infection. Clinically, TRIM68 expression is down-regulated, and the production of IL-1 family cytokines including IL-1α, IL-1β, IL-18 and IL-33 is highly elevated in lungs and LECs from allergic asthma patients, suggesting that TRIM68 indeed regulates allergic asthma. However, how TRIM68 expression is controlled by epigenetic modifications allowing responses to environmental stimuli is unknown. TRIM68 binds and induces the proteasome-dependent degradation of scaffold molecules, SYK and CARD9, to inhibit innate immune responses in allergic asthma. But the in vivo function of TRIM68 to regulate lung inflammation has not been studied. We hypothesize that TRIM68 down-regulation in LECs induces IL-1 family cytokines crucial for initial development as well as perpetuation of allergic asthma. We developed three specific aims in this proposal: (1) To dissect molecular pathways that control TRIM68 expression in LECs under normal and inflammatory conditions. (2) To define the mechanism by which TRIM68 inhibits IL-1 inflammation. (3) To investigate in vivo functions of TRIM68 in regulating LECs function in allergic asthma.

项目摘要 过敏性气道疾病如过敏性哮喘是一种T淋巴细胞控制的慢性疾病， 呼吸道炎症，通常是由于对吸入过敏原的免疫反应， 特征包括上皮损伤、气流阻塞和支气管高反应性。积累 有证据表明炎症小体活化和IL-1家族细胞因子包括IL-1α，IL-1β， IL-18和IL-33在过敏性哮喘发生中的作用此外，病毒性肺上皮细胞（LEC）感染， 最常见的是鼻病毒，主要与上皮细胞促进的哮喘急性发作有关。 IL-33。LEC是过敏原和粘膜免疫系统之间的物理屏障。重要的是，在 当激活时，LEC成为先天免疫样细胞以产生强大的促炎细胞因子。但 过敏性哮喘中LECs活化和IL-1家族细胞因子产生的分子基础仍不清楚。的 先天性免疫细胞使用传感器和适配器来识别病原体，从而产生细胞因子 对抗感染为了有效地控制和清除入侵者，必须调节这种免疫反应 微生物，同时最大限度地减少组织炎症。泛在化已经成为一种关键机制， 在先天免疫系统中控制这种反应。泛素化系统的关键组分是E3连接酶， 具体识别用于修改的衬底。我们最近发现，一个三方相互作用基序（TRIM） 家族成员E3连接酶TRIM 68在LEC中选择性表达。初步研究表明，TRIM 68 调节HDM提取物处理后LEC中炎性小体活化和全长IL-33的产生 或鼻病毒感染。临床上，TRIM 68表达下调，IL-1家族的产生减少， 过敏性哮喘患者肺和LEC中IL-1α、IL-1β、IL-18和IL-33等细胞因子水平显著升高 这表明TRIM 68确实调节过敏性哮喘。然而，TRIM 68的表达是如何影响 由允许对环境刺激作出反应的表观遗传修饰控制是未知的。TRIM 68结合 并诱导支架分子SYK和CARD 9的蛋白酶体依赖性降解，以抑制先天性 过敏性哮喘的免疫反应但TRIM 68调节肺部炎症的体内功能尚未被证实。 本文研究了我们假设TRIM 68在LEC中的下调诱导IL-1家族细胞因子的关键作用。 对于过敏性哮喘的初始发展以及永久化。我们制定了三个具体目标， 建议：（1）分析正常和低分化条件下控制晶状体上皮细胞TRIM 68表达的分子通路， 炎性条件。(2)确定TRIM 68抑制IL-1炎症的机制。(3)到 研究TRIM 68在过敏性哮喘中调节LEC功能的体内功能。