R01HL159804

Role of TNF Receptor 2 on Pulmonary Group 2 Innate Lymphoid Cells - Abstract

The long-term goal of this project is to develop better therapies for respiratory inflammation and allergic asthma. Group 2 innate lymphoid cells (ILC2) are a recently identified cell population producing type 2 cytokines in response to a growing number of environmental signals and epithelial cell-derived cytokines.

Studies show increased ILC2 activity in asthma and many widespread diseases, as ILC2s are sufficient to induce airway inflammation independent of adaptive immunity in mice. The proposed research plan is motivated by recent new observations from our laboratory and others that the TNF/TNFR2 axis controls ILC2-dependent airway inflammation (Cell Reports 2019, J Allergy Clin Immunol. 2020).

High levels of TNF are found in the lungs of asthmatic patients; however, anti-TNF therapy is generally associated with systemic toxicity due to the existence of two distinct functionally different receptors for TNF: TNFR1 and TNFR2. Our results suggest that TNF enhances the secretion of ILC2 effector cytokines IL-5 and IL-13 and increases survival via TNFR2 signaling, leading to airway inflammation. However, how the TNF/TNFR2 axis mechanistically affects ILC2s and subsequent development of airway inflammation remains to be explored.

Based on our data, we hypothesize that blocking TNFR2 on ILC2s induces an immunoregulatory phenotype fueling on a distinct metabolic source, together favoring the reduction of AHR. In Specific Aim 1 (SA1), we have designed several approaches to characterize the effects of TNF on ILC2 effector functions and lung inflammation. Our preliminary data suggest that TNFR2 is heterogeneously expressed on activated ILC2s. We will therefore characterize the transcription factors driving the effects of TNF in ILC2s using a combination of single-cell genomic and transcriptomic analysis.

Furthermore, data from our laboratory and others suggest that metabolic processes in ILC2s are dependent on the generation of energy from fatty acid oxidation (FAO) and oxidative phosphorylation. Interestingly, our results clearly show a metabolic shift towards glycolysis in TNFR2-/- ILC2s. Based on these results, we intend to assess glycolysis and FAO mechanisms in WT and TNFR2-/- ILC2s in SA2.

Finally, we previously showed that human ILC2s express TNFR2, and humanized ILC2 mice developed TNFR2-dependent AHR in response to TNF. Therefore, we intend to assess in SA3 the relevance of our findings in asthmatic patients. We will collect lung and blood ILC2s from carefully selected cohorts of mild/moderate, severe asthmatics, and healthy donors and correlate the levels of TNF in the BAL to the numbers of ILC2s/expression of TNFR2, as well as monitor other cells that express TNFR2.

These studies, based on strong preliminary data, will focus on developing novel therapy for allergic asthma. In order to achieve these results, we have assembled a team including leading experts in lung biology and the chief of clinical pulmonology to complement our extensive experience in pre-clinical models.

University Of Southern California

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

California United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 286% from $784,241 to $3,029,887.