# Studies of a new checkpoint regulator in controlling lung inflammation

> **NIH NIH R56** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $242,250

## Abstract

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.

## Key facts

- **NIH application ID:** 10229265
- **Project number:** 1R56AI148215-01A1
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Zhiqiang Zhang
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $242,250
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229265

## Citation

> US National Institutes of Health, RePORTER application 10229265, Studies of a new checkpoint regulator in controlling lung inflammation (1R56AI148215-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10229265. Licensed CC0.

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