Allergic airway inflammation is a hallmark of asthma, a disease that is a significant cause of morbidity in the US. Group 2 innate lymphoid cells (ILC2) produce cytokines that drive the initial phase of allergic airway inflammation. ILC2 are activated by cytokines such as thymic stromal lymphopoietin (TSLP) that are produced in response to airway challenge with Alternaria alternata, a widespread fungal aeroallergen that has been linked to severe asthma exacerbations. To date, there are no known negative regulators of lung ILC2 that are approved by the FDA. However, our novel preliminary data reveals that endogenous PGI2 critically inhibits both airway TSLP expression and the lung expression of IL-5 and IL-13, cytokines expressed by lung ILC2, following intratracheal (IT) challenge of mice with the allergen extract of Alternaria alternata. Additional preliminary data suggests that exogenous PGI2 inhibits innate immune cell expression of TSLP in both mouse and human cells. These preliminary data lead us to propose the hypothesis that PGI2 negatively regulates the expression and signaling of TSLP in response to Alternaria airway challenge and, as a result, inhibits the development and function of lung ILC2. This proposal will determine how PGI2 regulates the activation of host innate immune cells and signaling pathways to the microbial antigens in Alternaria alternata that lead to allergic inflammatory responses. The proposed studies are paradigm shifting in that they will determine the role of PGI2 in blocking IL-5 and IL-13 expression by lung ILC2 and the signaling pathways responsible for this inhibition. These proposed studies are clinically relevant in that we will define potential mechanisms by which PGI2, which is currently FDA approved for the treatment of pulmonary hypertension, may be effective in the treatment of allergic airway inflammatory diseases such as asthma. In addition, we will define how dietary supplementation of ?-3 fatty acid, which reduces endogenous PGI2, regulates the early innate allergic immune response to Alternaria alternata challenge. Such diets have been recommended as asthma therapy, but our preliminary data leads us to hypothesize that ?-3 fatty acid dietary supplementation increases airway TSLP expression and lung ILC2 cell cytokine secretion, thus exacerbating allergic airway inflammation. The proposed studies will advance the field by defining mechanisms that negatively regulate the early innate immune response to the protease containing allergens such as Alternaria alternata.

Public Health Relevance

Allergic airway inflammation is a hallmark of asthma, one of the most common chronic diseases in the United States. Very recently, the Group 2 innate lymphoid cell (ILC2) was discovered in both in mice and in people. The ILC2 produces large quantities of specific proteins called cytokines that are important in the development of allergic inflammation. Our preliminary data suggests that a medication that is currently being used for the treatment of patients with pulmonary hypertension, prostaglandin (PG)I2, may be an important inhibitor of the inflammatory function of ILC2. Our proposal will define the mechanisms by which PGI2 blocks the initial phases of allergic airway inflammation and may be a novel and effective treatment for asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI111820-01
Application #
8704022
Study Section
Special Emphasis Panel (ZRG1-CVRS-N (02))
Program Officer
Davidson, Wendy F
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$391,875
Indirect Cost
$141,875
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212