Severe asthma is a complex heterogeneous disease, which poorly responds to corticosteroids (CS), the current standard of care for asthma. In a previous study, we reported that bronchoalveolar lavage (BAL) cells in >50% of subjects with severe asthma (SA) secrete high levels of IFN-? from CD4+ T cells despite treatment of the subjects with high doses of inhaled CS, often combined with oral CS. In a recent follow-up study to understand the molecular mechanisms that promote a persistent Th1high phenotype in SA, we have shown an essential role for the transcription factor IRF5 in promoting IL-12 production from lung dendritic cells (DCs) and macrophages (M?s) to elicit high levels of IFN-? production from T cells. In another study published recently, we show that SA subjects with a Th1high profile harbor higher levels of expression of the Th1-recruiting chemokine CXCL10 in their airways compared to mild asthma subjects, strongly associated with IFN-? expression, frequency of oral CS use, and expression of mast cell-specific proteases. Chromatin immunoprecipitation (ChIP) assay used to determine high CXCL10 levels in SA revealed recruitment of both STAT1 to and GR to the CXCL10 promoter with no accompanying suppression of CXCL10 mRNA expression. While CS were unable to suppress IFN-?-induced CXCL10 mRNA and protein levels in monocytes, IL-10 completely inhibited CXCL10 gene expression in the context of IFN-? and CS, an effect not realized in many severe asthmatics. In new data generated using RNA-seq approaches, we show downregulation of the negative regulator of TGF-?1-mediated signaling, Smad7, and upregulation of c-Myc, in lungs of mice subjected to the SA model, which may impact mast cells and airway remodeling. Indeed in our recent report we have shown a strong correlation between CXCL10 mRNA and mast cell signatures in humans and mice. Mast cells produce cysteinyl leukotrienes (CysLTs), and our RNA-seq data show that IFN-? selectively upregulates expression of the CysLT receptor, CySLTR2, in the lung. Collectively, these studies lead us to hypothesize that the IRF-5-IFN-?-CXCL10 axis in the context of CS induces a feed-forward loop promoting a Th1high phenotype that impacts lung function and airway remodeling involving mast cells. Although refractory to CS, the Th1high state is sensitive to IL-10. To test this hypothesis we will:
Aim 1. Establish IRF5 in lung APCs as a sustainer of Th1 (IFN-?) effector function and identify IRF5 SNPs in humans.
Aim 2. Determine the role of specific IFN-?-regulated molecules and mast cells in disease pathogenesis in the SA model.
Aim 3. Investigate defective IL-10 production in T cells in humans with SA and study inhibition by IL-10 of CS- refractory CXCL10 gene expression induced by IFN-?.

Public Health Relevance

The goal of this application is to utilize novel information generated during the previous cycle of this application to study the role of IRF-5-IFN-?-CXCL10 axis in mediating immune dysfunction in severe asthma using human samples and a mouse model of severe asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Noel, Patricia
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University of Pittsburgh
Internal Medicine/Medicine
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Oriss, Timothy B; Raundhal, Mahesh; Morse, Christina et al. (2017) IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice. JCI Insight 2:
Das, Sudipta; Raundhal, Mahesh; Chen, Jie et al. (2017) Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response. JCI Insight 2:
Gauthier, Marc; Chakraborty, Krishnendu; Oriss, Timothy B et al. (2017) Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias. JCI Insight 2:
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Raundhal, Mahesh; Morse, Christina; Khare, Anupriya et al. (2015) High IFN-? and low SLPI mark severe asthma in mice and humans. J Clin Invest 125:3037-50
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Khare, Anupriya; Chakraborty, Krishnendu; Raundhal, Mahesh et al. (2015) Cutting Edge: Dual Function of PPAR? in CD11c+ Cells Ensures Immune Tolerance in the Airways. J Immunol 195:431-5

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