IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice
Timothy B. Oriss, … , Prabir Ray, Anuradha Ray
Timothy B. Oriss, … , Prabir Ray, Anuradha Ray
Published May 18, 2017
Citation Information: JCI Insight. 2017;2(10):e91019. https://doi.org/10.1172/jci.insight.91019.
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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 1

Upregulation of IRF5 expression in the airways of severe asthma patients and in an experimental model and its role in airway hyperresponsiveness and airway inflammation.

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Upregulation of IRF5 expression in the airways of severe asthma patients...
(A, upper panel) Human bronchoalveolar lavage (BAL) cells were obtained from subjects undergoing bronchoscopy. Subjects were clinically classified as healthy controls, mild to moderate asthmatics (M/MOD), or severe asthmatics (SA). qRT-PCR was performed on total BAL cell mRNA for IRF5 expression (n = 7 SA, 6 M/MOD, 10 healthy controls). (A, lower panel) Mice were sensitized with house dust mite antigen (HDM) alone (M/MOD model) or HDM + cyclic diguanosine monophosphate (c-di-GMP) (SA model). Irf5 mRNA expression was assayed by qRT-PCR in total lung homogenates. In each case, expression level relative to Hprt1 is shown. (B–F) WT or IRF5–/– mice were subjected to the model of SA or M/MOD asthma as shown. (B) Periodic acid-Schiff (PAS) stains of lung sections along with inflammation scores in the perivascular and peribronchial regions. Scale bars: 100 μm (n = 7 per group). (C) Assessment of airway hyperresponsiveness (AHR) in mice subjected to the SA model. Shown are central airway resistance (Newtonian resistance, Rn) values. (D) AHR in the M/MOD model. (E) Differential counts of BAL cells collected from WT and IRF5–/– mice subjected to the SA model. (F) Differential BAL cell counts similarly determined from WT mice subjected to either the SA or the M/MOD model. For all cell differentials, a total of at least 300 cells were counted and the results shown are expressed as percentage of each cell type recovered (Macs, macrophages; Lymphs, lymphocytes; Eos, eosinophils; PMNs, neutrophils). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 by 1-way ANOVA with Bonferroni’s multiple comparison test. n = 6–8 mice per group (C–F). Data are the mean ± SEM and are representative of 3 independent experiments. ns, not significant.