Project 1 (Broide) will investigate innate pathways that contribute to airway inflammation and airway remodeling in asthma. This project will focus on increasing our understanding of how a novel innate cell cytokine (Folistatin Like Protein-1 or FSL-1) as well as a novel innate cell population of pro-inflammatory natural helper cells (NHC) (small mononuclear cells that express high levels of Th2 cytokines, but no markers for T cells, NK cells, mononuclear cells, macrophages, mast cells) mediate important aspects of allergen induced airway inflammation and remodeling. Studies will examine how allergen exposure in atopic asthma activates these two novel interconnected innate pathways to promote airway inflammation and remodeling (i.e. activation of natural helper cells to express Th2 cytokines that subsequently activate M2 macrophages to express FSL-1 a pro-inflammatory and pro-remodeling gene with receptors on smooth muscle and blood vessels). The importance of these novel innate pathways to asthma will be examined by studying levels of their expression in asthma compared to healthy controls, as well as in asthmatics challenged with allergen or rhinovirus. In addition we will determine the stimuli that induce their expression, the distribution of receptors that mediate their activation, and the profile of mediators released following their activation that are important to inflammation and remodeling. Finally, although the major focus of this project will be on studying human asthmatics, mouse models will be used to answer mechanistic questions that are not ethical to perform in humans (such as administration of anti-FSL-1 Ab, and adoptive transfer or depletion of NHC). This research project will interact with both Project 2 (Croft), Project 3 (Zuraw) and Core B to gain insight into how allergen and viral triggers of asthma contribute to airway inflammation and remodeling in asthma.

Public Health Relevance

Inhalation of airborne allergens such as cat and dust mite or respiratory viruses may result in damage and scarring of the bronchial tubes in susceptible asthmatics. This project will provide increased understanding of the cause of this scarring and suggest potential ways to identify asthmatics at risk for developing scarring of their lungs, or potential new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070535-08
Application #
8516966
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$269,929
Indirect Cost
$44,426
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Herro, Rana; Shui, Jr-Wen; Zahner, Sonja et al. (2018) LIGHT-HVEM signaling in keratinocytes controls development of dermatitis. J Exp Med 215:415-422
Chen, Jun; Miller, Marina; Unno, Hirotoshi et al. (2018) Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. J Allergy Clin Immunol 142:207-218.e6
White, Andrew A; Doherty, Taylor A (2018) Role of group 2 innate lymphocytes in aspirin-exacerbated respiratory disease pathogenesis. Am J Rhinol Allergy 32:7-11
Mehta, Amit K; Gracias, Donald T; Croft, Michael (2018) TNF activity and T cells. Cytokine 101:14-18
Karta, Maya R; Rosenthal, Peter S; Beppu, Andrew et al. (2018) ?2 integrins rather than ?1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung. J Allergy Clin Immunol 141:329-338.e12
Mehta, A K; Doherty, T; Broide, D et al. (2018) Tumor necrosis factor family member LIGHT acts with IL-1? and TGF-? to promote airway remodeling during rhinovirus infection. Allergy 73:1415-1424
Doherty, Taylor A; Broide, David H (2018) Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines. J Allergy Clin Immunol 141:1587-1589
da Silva Antunes, Ricardo; Mehta, Amit K; Madge, Lisa et al. (2018) TNFSF14 (LIGHT) Exhibits Inflammatory Activities in Lung Fibroblasts Complementary to IL-13 and TGF-?. Front Immunol 9:576
Unno, Hirotoshi; Miller, Marina; Rosenthal, Peter et al. (2018) Activating transcription factor 6? (ATF6?) regulates airway hyperreactivity, smooth muscle proliferation, and contractility. J Allergy Clin Immunol 141:439-442.e4

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