Severe asthma is a difficult disease to control by corticosteroids (CSs), which remain the mainstay of asthma therapy. This differential outcome in response to CS therapy, even when used at a high dose orally or parenterally, suggests a fundamental difference in the nature of the inflammatory response in the two subclasses of asthmatics. To understand the mechanisms and mediators that promote CS-refractory asthma, we have developed a mouse model of disease in which both airway inflammation and CS-unresponsiveness mimic the severe asthma phenotype in humans including high IFN-?/Th1, IL-27 and IL-17 responses. Our model involves exposure of mice to an allergen (house dust mite-HDM) with a mucosal adjuvant, cyclic-di- GMP (c-di-GMP), to promote a mixed granulocytic infiltration in the airways with induction of significantly higher IFN-? and IL-17 responses in the lung-draining lymph nodes and the lungs of the mice but a lower IL-13/IL-5 response compared to that induced by HDM alone. Administration of the CS, dexamethasone (Dex), in HDM+c-di-GMP-exposed mice did not subdue the IFN-?/IL-17/IL-13 response or the airway neutrophilia but partially attenuated the eosinophilia. Airway hyperreactivity in these mice was also only partially attenuated by CS. Collectively, our data lead us to hypothesize that 1) CS-refractory asthma is orchestrated by a high Th1 response often accompanied by a Th17 response that promotes airway neutrophilia. 2) Increased production of key Th1- and Th17-skewing cytokines such as IL-27 and IL-12 (Th1) and IL-6 and IL-23 (Th17) from innate cells such as dendritic cells (DCs) underlies the heightened Th1 and Th17 response. 3) The transcription factors IRF5, recently implicated in IL-6, IL-12 and IL-23 production from M1 macrophages, and STAT1, downstream of IFNs and IL-27, are involved in driving Th1 and Th17 development. The idea that CS refractory severe asthma might involve collaboration between IFN-?, IL-27 and Th17 cytokines in severe asthma has not been appreciated or investigated in prior studies. To address our hypotheses we will:
Aim 1. Investigate the role of the Th1 and Th17 pathways in promoting the CS-refractory severe asthma phenotype characterized by mixed granulocytic airway inflammation.
Aim 2. Determine the mechanisms by which high Th1 and Th17 responses are induced by exposure to HDM and c-di-GMP via effects on innate cells.
Aim 3. Identify the cellular source and role of IL-27 in initiation and perpetuation of CS-refractory severe asthma phenotype. The mouse model in conjunction with genetically engineered mice will allow us to investigate the role of key mediators in promoting the severe asthma phenotype. The model will be useful to test novel therapeutic modalities as and when they become available. Additionally, RNA sequencing data generated from this study will identify novel networks in SA for future interrogation in the experimental model and in translational studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113956-02
Application #
8601947
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2013-01-07
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$359,711
Indirect Cost
$116,929
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Oriss, Timothy B; Krishnamoorthy, Nandini; Raundhal, Mahesh et al. (2014) Cutting Edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response. J Immunol 192:5471-5
Oriss, Timothy B; Krishnamoorthy, Nandini; Ray, Prabir et al. (2014) Dendritic cell c-kit signaling and adaptive immunity: implications for the upper airways. Curr Opin Allergy Clin Immunol 14:7-12
Ray, Anuradha; Chakraborty, Krishnendu; Ray, Prabir (2013) Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation. Front Cell Infect Microbiol 3:52
Khare, Anupriya; Krishnamoorthy, Nandini; Oriss, Timothy B et al. (2013) Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance. J Immunol 191:25-9