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 3

Migratory DCs in lymph nodes of IRF5–/– mice are deficient in IL-12 and IL-6 production during the sensitization phase in model of severe asthma.

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Migratory DCs in lymph nodes of IRF5–/– mice are deficient in IL-12 and ...
Mice were sensitized as in Figure 2. (A) Migratory DCs (migDCs) with the phenotype CD11c+/MHC class IIhi were purified by fluorescence-activated cell sorting. migDCs contained both CD11b+ and CD103+ cells at the percentages indicated. (B) qRT-PCR was performed on purified migDCs for Il12p35, Il12p40, Il6, and Il10. Data are the mean ± SEM showing proportion of expression in IRF5–/– mice relative to WT mice for 2 independent, combined experiments. Data are the mean ± SEM of 7 mice per group and representative of 2 independent experiments. *P ≤ 0.05, **P ≤ 0.01, unpaired Student’s t test. (C) IL-12p40-EYFP reporter mice, either untreated or sensitized with house dust mite antigen (HDM) + cyclic diguanosine monophosphate (c-di-GMP), were assessed for lymph node expression of IL-12p40 in CD11b+ and CD103+ migDCs. Using proportions obtained by flow cytometry and total cell recovery, the number of DC subtypes found in each group was calculated on a per mouse basis and are estimated at: CD11b+ untreated, 122 cells; CD11b+ HDM + c-di-GMP–treated, 2,649 cells; CD103+ untreated, 74 cells; and CD103+ HDM + c-di-GMP–treated, 1,024 cells. Data are pooled from 3 mice per group. cDCs, conventional DCs; rDCs, resident DCs; MFI, mean fluorescence intensity; ns, not significant.