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.

项目概要 过敏性气道疾病，如过敏性哮喘，是由 T 淋巴细胞控制的慢性疾病， 呼吸道炎症，通常是由对吸入过敏原的免疫反应引起的，而关键 特征包括上皮损伤、气流阻塞和支气管高反应性。积累中 有证据表明炎症小体激活和 IL-1 家族细胞因子（包括 IL-1α、IL-1β、 IL-18 和 IL-33 在过敏性哮喘发展中的作用。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恶化有关 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，之后 激活后，LEC 成为先天免疫样细胞，产生强大的促炎细胞因子。然而， 过敏性哮喘中 LEC 激活和 IL-1 家族细胞因子产生的分子基础仍然难以捉摸。这 先天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 防止感染。必须调节这种免疫反应才能有效控制和消除入侵 微生物，同时最大限度地减少组织炎症。泛素化已成为一种关键机制 控制先天免疫系统中的这种反应。泛素化系统的关键组成部分是 E3 连接酶 特异性识别要修饰的底物。我们最近发现了一个三方相互作用基序（TRIM） 家族成员 E3 连接酶 TRIM68 在 LEC 中选择性表达。我们的初步研究表明 TRIM68 HDM 提取物处理后，调节 LEC 中炎症小体的激活和全长 IL-33 的产生 或鼻病毒感染。临床上，TRIM68表达下调，IL-1家族产生 过敏性哮喘引起的肺部和 LEC 中细胞因子（包括 IL-1α、IL-1β、IL-18 和 IL-33）高度升高 患者，表明 TRIM68 确实可以调节过敏性哮喘。然而，TRIM68 的表达方式是怎样的？ 由表观遗传修饰控制，允许对环境刺激做出反应尚不清楚。 TRIM68 结合 并诱导支架分子 SYK 和 CARD9 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 TRIM68 调节肺部炎症的体内功能尚未见报道。 被研究过。我们假设 LEC 中 TRIM68 下调诱导 IL-1 家族细胞因子至关重要 用于过敏性哮喘的最初发展和持续。我们在此制定了三个具体目标 建议：（1）剖析正常和不同条件下LECs中控制TRIM68表达的分子通路。 炎症状况。 (2)明确TRIM68抑制IL-1炎症的机制。 (3) 至 研究 TRIM68 在调节过敏性哮喘 LEC 功能中的体内功能。