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（例如过敏性哮喘）是由T淋巴细胞控制的慢性疾病 呼吸道的炎症，通常是由于对吸入过敏原的免疫反应而引起的，关键 特征包括上皮损伤，气流异常和支气管高反应性。累积 有证据表明，炎性体激活和IL-1家族细胞因子包括IL-1α，IL-1β， IL-18和IL-33在过敏性哮喘的发展中。此外，病毒肺上皮细胞（LEC）感染， 鼻病毒最常经常与上皮促进的哮喘恶化有关 IL-33。 LEC是过敏原与粘膜免疫系统之间的物理障碍。重要的是，之后 激活，LEC成为先天免疫样细胞，产生可靠的促炎细胞因子。但是， LECS激活和IL-1家族细胞因子在过敏性哮喘中产生的分子基础仍然难以捉摸。 先天免疫细胞使用传感器和衔接子识别病原体，导致细胞因子的产生 反感染。必须调节这种免疫反应以有效控制和消除入侵 微生物，同时最大程度地减少组织注射。泛素化已成为关键机制 控制先天免疫系统中的这一反应。泛素化系统的关键组成部分是E3连接酶 我们最近发现三层相互作用图案（TRIM） 家庭成员E3连接酶Trim68在LEC中有选择地表达。我们的初步研究表明TRIM68 在HDM提取物处理后，在LEC中调节炎症体激活和全长IL-33的产生 或鼻病毒感染。临床上，TRIM68表达被下调，IL-1家族的产生 包括IL-1α，IL-1β，IL-18和IL-33在内的细胞因子在过敏性哮喘中高度升高 患者，表明TRIM68确实调节过敏性哮喘。但是，trim68表达方式 由允许对环境刺激的反应的表观遗传修饰控制的是未知的。 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。但是TRIM68的体内功能尚未 我们假设LEC中的TRIM68下调会影响IL-1家族细胞因子至关重要 为了初步发展以及过敏性哮喘的永久性。我们在这方面开发了三个特定的目标 建议：（1）剖析控制正常和在正常和 炎症条件。 （2）定义TRIM68抑制IL-1注射的机制。 （3）到 研究TRIM68在调节过敏性哮喘中的LEC功能中的体内功能。