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 8

In vivo administration of human IL-1RA improves lung function during experimental fungal–associated allergic airway inflammation.

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In vivo administration of human IL-1RA improves lung function during exp...
C57BL/6 WT mice were chronically exposed to A. fumigatus as described in Methods and treated daily from days 0–16 with 10 mg/kg or 50 mg/kg human recombinant IL-1RA (Kineret/anakinra) or vehicle i.p. Twenty-four hours after the last organism challenge, (A and C) Airway (Newtonian) resistance and (B and D) 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 expressed as mean ± SEM. *P < 0.05 and ***P < 0.001 (2-way ANOVA). (E–G) Twenty-four hours after the last organism challenge, the right lungs were collected and enzymatically digested, and unfractionated lung cells were cultured for 24 hours in the presence of A. fumigatus conidia at a cell/organism ratio of 1:1. (E) IFN-γ, CXCL9 and CXCL10 levels, (F) IL-17A and IL-22 levels, and (G) IL-4 and IL-5 levels in lung digest cell culture supernatants from vehicle treated vs. Kineret/anakinra were quantified by MilliPlex or ELISA; Milliplex was employed for all cytokines except IL-22, and ELISA was used for IL-22. The figures illustrate cumulative data from 2 independent studies (n = 4–5 mice per group per study). Data are 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. *P < 0.05, **P < 0.01, and ***P < 0.001 (2-tailed Student’s t test). (H) 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). Data are 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. *P < 0.05, **P < 0.01, and ***P < 0.001 (2-tailed Student’s t test).