IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice
Timothy B. Oriss, Mahesh Raundhal, Christina Morse, Rachael E. Huff, Sudipta Das, Rachel Hannum, Marc C. Gauthier, Kathryn L. Scholl, Krishnendu Chakraborty, Seyed M. Nouraie, Sally E. Wenzel, Prabir Ray, Anuradha Ray
Timothy B. Oriss, Mahesh Raundhal, Christina Morse, Rachael E. Huff, Sudipta Das, Rachel Hannum, Marc C. Gauthier, Kathryn L. Scholl, Krishnendu Chakraborty, Seyed M. Nouraie, Sally E. Wenzel, Prabir Ray, Anuradha Ray
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Research Article Pulmonology

IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice

Abstract

Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1–dominated (IFN-γ–dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ– and IL-17–producing CD4+ T cells and IRF5–/– mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage disease in a subset of severe asthmatics.

Authors

Timothy B. Oriss, Mahesh Raundhal, Christina Morse, Rachael E. Huff, Sudipta Das, Rachel Hannum, Marc C. Gauthier, Kathryn L. Scholl, Krishnendu Chakraborty, Seyed M. Nouraie, Sally E. Wenzel, Prabir Ray, Anuradha Ray

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Figure 6

Combination of IRF5 deficiency and corticosteroid treatment alleviates multiple features of severe asthma.

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Combination of IRF5 deficiency and corticosteroid treatment alleviates m...
WT or IRF5–/– mice were subjected to the full 28-day model of severe asthma (SA) with or without (control [C]) treatment with (Dex). (A) Central airway resistance (Newtonian resistance, Rn) measurements are shown (6–8 mice were used per group). (B) Levels of total serum IgE and (C) house dust mite antigen–specific (HDM-specific) IgG2a and IgG1. (D) Percentage of eosinophils and neutrophils in bronchoalveolar lavage (BAL) cells. n = 5–6 mice per group (B–D). Data are the mean ± SEM and each experiment was performed at least twice independently. P ≤ 0.05, **P ≤ 0.01 using the Mann-Whitney U test.