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 2

Decreased IFN-γ in the lymph nodes of IRF5–/– mice in the sensitization phase of the severe asthma model.

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Decreased IFN-γ in the lymph nodes of IRF5–/– mice in the sensitization ...
Lymph nodes were harvested 24 hours following immunization with house dust mite antigen (HDM) + cyclic diguanosine monophosphate (c-di-GMP) on days 1, 3, and 5. (A) Total lymph node cells were restimulated in vitro for 72 hours with HDM and levels of IFN-γ, IL-17A, and IL-12p40 in the culture supernatants were assessed by ELISA (n = 8 WT, 8–12 IRF5–/– mice). (B) IFN-γ, IL-17A, IL-10, and IL-12p40 production by total lymph node cells obtained from sensitized mice cultured with HDM in the presence of either neutralizing antibody against IL-10 or appropriate isotype control antibody (cells pooled from 4 to 5 mice per group and then cultured in triplicate wells). (C) Lymph node migratory DCs (migDCs) (See Figure 3 for details) and lymph node CD4+ T cells were both isolated by fluorescence-activated cell sorting and cultured together with HDM for 72 hours. IFN-γ, IL-17A, IL-10, and IL-12p40 production was assessed by ELISA. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 by Mann-Whitney U test (A and C) or unpaired Student’s t test (B). Data are the mean ± SEM and are representative of 3 independent experiments.