Studies of a new checkpoint regulator in controlling lung inflammation

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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.