IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation
Matthew S. Godwin, Kristen M. Reeder, Jaleesa M. Garth, Jonathan P. Blackburn, MaryJane Jones, Zhihong Yu, Sadis Matalon, Annette T. Hastie, Deborah A. Meyers, Chad Steele
Matthew S. Godwin, Kristen M. Reeder, Jaleesa M. Garth, Jonathan P. Blackburn, MaryJane Jones, Zhihong Yu, Sadis Matalon, Annette T. Hastie, Deborah A. Meyers, Chad Steele
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Research Article Immunology Pulmonology

IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation

Abstract

Severe asthma with fungal sensitization (SAFS) defines a subset of human asthmatics with allergy to 1 or more fungal species and difficult-to-control asthma. We have previously reported that human asthmatics sensitized to fungi have worse lung function and a higher degree of atopy, which was associated with higher IL-1 receptor antagonist (IL-1RA) levels in bronchoalveolar lavage fluid. IL-1RA further demonstrated a significant negative association with bronchial hyperresponsiveness to methacholine. Here, we show that IL-1α and IL-1β are elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with IL-1α, IL-1β, or IL-1RA in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that IL-1R1 signaling promotes type 1 (IFN-γ, CXCL9, CXCL10) and type 17 (IL-17A, IL-22) responses that were associated with neutrophilic inflammation and increased airway hyperreactivity. Each of these were exacerbated in the absence of IL-1RA. Administration of human recombinant IL-1RA (Kineret/anakinra) during fungal-associated allergic airway inflammation improved airway hyperreactivity and lowered type 1 and type 17 responses. Taken together, these data suggest that IL-1R1 signaling contributes to fungal asthma severity via immunopathogenic type 1 and type 17 responses and can be targeted for improving allergic asthma severity.

Authors

Matthew S. Godwin, Kristen M. Reeder, Jaleesa M. Garth, Jonathan P. Blackburn, MaryJane Jones, Zhihong Yu, Sadis Matalon, Annette T. Hastie, Deborah A. Meyers, Chad Steele

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Figure 3

IL-1 receptor antagonist regulates the severity of experimental fungal–associated allergic airway inflammation.

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IL-1 receptor antagonist regulates the severity of experimental fungal–a...
C57BL/6 WT and IL-1 receptor antagonist–deficient (Il1rn–/–) mice were chronically exposed to A. fumigatus as described in the Methods. Twenty-four hours after the last organism challenge, (A) airway (Newtonian) resistance and (B) total lung resistance was analyzed via mechanical ventilation using the flexiVent pulmonary function system. The figures illustrate cumulative data from 2 independent studies (n = 4–5 mice per group per study). Data are expressed as mean ± SEM. ***P < 0.001 (2-way ANOVA). Representative (C) H&E- and PAS-stained lung sections from WT (left images) and Il1rn–/– (right images) mice. Original magnification, 20×. Scale bar: 100 μm. (D) Compliance, (E) tissue damping, and (F) tissue elastance was analyzed via mechanical ventilation using the flexiVent pulmonary function system. The figures illustrate cumulative data from 2 independent studies (n = 4–5 mice per group per study). Data expressed as mean ± SEM. ***P < 0.001 (2-way ANOVA). (G) Twenty-four hours after the last challenge, the left lungs were collected, and Muc5ac and Gob5 gene expression was quantified by real-time PCR and normalized to HPRT. Gene expression presented as 2−ΔΔCt. The figure illustrates cumulative data from 2 independent studies (n = 4 mice per group per study). Quantitative data is represented as a box-and-whisker plot, with bounds ranging from 25th to 75th percentile, the line representing the median, whiskers ranging from minimum to maximum values, and + indicating the mean.