The goal of the proposed research is to identify novel mechanisms that regulate type 2 innate lymphoid cells (ILC2). ILC2 are a recently discovered population of lineage-negative lymphocytes that produce Th2 cytokines in response to epithelial cytokines IL-33 and TSLP. ILC2 contribute to an asthma phenotype in animal models and are present in human lungs. Specifically, we hypothesize that the RNA-binding protein RBM3 controls human and mouse ILC2 Th2 cytokine production and innate type 2 lung responses through Th2 cytokine mRNA stabilization. We will administer allergen, IL-33, and TSLP challenges to the airways of WT and RBM3 knockout mice and assess lung ILC2 Th2 cytokine production and proliferation, as well as levels of BAL eosinophils, epithelial mucus production, peribronchial infiltration and airway hyperresponsiveness. We will also perform ILC2 adoptive transfer studies and generate RBM3 deficient IL-13 reporter mice to define the role of RBM3 in ILC2 during allergen, IL-33, and TSLP-induced airway inflammation. We will perform in vitro studies with purified ILC2 from WT and RBM3 knockout mice as well as human RMB3 siRNA knockdown ILC2 stimulated with IL-33 and TSLP and assess levels of ILC2 Th2 cytokine production and proliferation. Further, we will perform mRNA stability assays to determine whether RBM3 controls ILC2 function by stabilizing Th2 cytokine mRNAs. We expect to find that RMB3 promotes ILC2 Th2 cytokine mRNA stability and controls ILC2 Th2 cytokine production in vitro and in vivo. The novelty of the proposed studies includes use of novel reagents (RBM3-/-, RBM3-/-RAG2-/-, and RBM3-/-/YFP-IL-13 reporter mice) and uncovering a novel pathway (RNA binding protein) regulating a recently discovered cell type (ILC2) that contributes to allergic inflammation. Importantly, the discovery of molecules that regulate ILC2 function may reveal novel therapeutic targets to reduce ILC2 activation in asthma and allergic disease.

Public Health Relevance

Asthma currently afflicts 7% of the US population and identification of novel targets is critical in order to develop future treatments for those who do ot respond to available therapy. A new white blood cell termed the type 2 innate lymphoid cell or ILC2 has recently been discovered in human lungs and contributes to asthma features in animal models. We propose to identify a new pathway used by the ILC2 to induce lung inflammation that may represent a therapeutic target for asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114585-05
Application #
9589455
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Davidson, Wendy F
Project Start
2014-11-10
Project End
2019-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Doherty, Taylor A; Broide, David H (2017) Pathways to limit group 2 innate lymphoid cell activation. J Allergy Clin Immunol 139:1465-1467
Lund, Sean J; Portillo, Alex; Cavagnero, Kellen et al. (2017) Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation. J Immunol 199:1096-1104
Cavagnero, Kellen; Doherty, Taylor A (2017) Cytokine and Lipid Mediator Regulation of Group 2 Innate Lymphoid Cells (ILC2s) in Human Allergic Airway Disease. J Cytokine Biol 2:
Eastman, Jacqueline J; Cavagnero, Kellen J; Deconde, Adam S et al. (2017) Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 140:101-108.e3
Kim, Alexander S; Doherty, Taylor A; Karta, Maya R et al. (2016) Regulatory B cells and T follicular helper cells are reduced in allergic rhinitis. J Allergy Clin Immunol 138:1192-1195.e5
Tkachenko, Eugene; Rawson, Renee; La, Elizabeth et al. (2016) Rigid substrate induces esophageal smooth muscle hypertrophy and eosinophilic esophagitis fibrotic gene expression. J Allergy Clin Immunol 137:1270-1272.e1
Kim, Alexander S; Doherty, Taylor A (2016) New and emerging therapies for asthma. Ann Allergy Asthma Immunol 116:14-7
Karta, Maya R; Broide, David H; Doherty, Taylor A (2016) Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease. Curr Allergy Asthma Rep 16:8
Miller, Marina; Beppu, Andrew; Rosenthal, Peter et al. (2015) Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M. J Immunol 195:3546-56
Doherty, Taylor A; Baum, Rachel; Newbury, Robert O et al. (2015) Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis. J Allergy Clin Immunol 136:792-794.e3

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