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 4

Neutrophils and their associated inflammatory mediators are differentially regulated by IL-1R1 and IL-1RA during experimental fungal–associated allergic airway inflammation.

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Neutrophils and their associated inflammatory mediators are differential...
C57BL/6 WT, IL-1 receptor–deficient (Il1r1–/–), and IL-1 receptor antagonist–deficient (Il1rn–/–) mice were chronically exposed to A. fumigatus as described in the Methods. (A and B) Twenty-four hours after the last challenge, lung cells from (A) WT and Il1r1–/– mice and from (B) WT and Il1rn–/– mice were isolated by bronchoalveolar lavage, enumerated, Fc-blocked, stained with a live/dead staining kit, and stained for neutrophils (CD45+, CD11b+, Ly-6G+, Siglec F–). The figures illustrate cumulative data from 2–3 independent studies (n = 4–5 mice per group per study). (C and D) Twenty-four hours after the last challenge, right lungs were collected and enzymatically digested, and unfractionated lung cells were cocultured with A. fumigatus conidia for 24 hours at a cell/organism ratio of 1:1. IL-17A and IL-22 levels in lung digest cell culture supernatants from (C) WT and Il1r1–/– mice and (D) WT and Il1rn–/– mice were quantified by MilliPlex or ELISA. The figures illustrate cumulative data from 2 independent studies (n = 3 mice per group per study). (E and F) Samples obtained as described for C and D. G-CSF, CCL3, and CCL4 levels in lung digest cell culture supernatants from (E) WT and Il1r1–/– mice and (F) WT and Il1rn–/– mice were quantified by MilliPlex. The figures illustrate cumulative data from 3 independent studies (n = 3–5 mice per group per study). For all graphs, quantitative 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).