High IFN-γ and low SLPI mark severe asthma in mice and humans
Mahesh Raundhal, … , Prabir Ray, Anuradha Ray
Mahesh Raundhal, … , Prabir Ray, Anuradha Ray
Published June 29, 2015
Citation Information: J Clin Invest. 2015;125(8):3037-3050. https://doi.org/10.1172/JCI80911.
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Research Article Pulmonology

High IFN-γ and low SLPI mark severe asthma in mice and humans

Abstract

Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng–/– mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra–/– mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

Authors

Mahesh Raundhal, Christina Morse, Anupriya Khare, Timothy B. Oriss, Jadranka Milosevic, John Trudeau, Rachael Huff, Joseph Pilewski, Fernando Holguin, Jay Kolls, Sally Wenzel, Prabir Ray, Anuradha Ray

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Figure 6

IFN-γ controls AHR in the SA mouse model.

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IFN-γ controls AHR in the SA mouse model. (A–D) WT and Ifng–/– mice were...
(A–D) WT and Ifng–/– mice were subjected to the SA model, and different end points were analyzed 24 hours after the final allergen challenge. (A) AHR in WT and Ifng–/– mice after MCh challenge. ****P ≤ 0.0001, 1-way ANOVA with Tukey’s post-hoc test. (B) Differential cell counts in BAL fluid cytospins showing total cells, eosinophils, macrophages, neutrophils, and lymphocytes. *P ≤ 0.05; **P ≤ 0.01, Student’s unpaired t test. (C) PAS staining of lung sections and (D) cytokine levels in total lungs. ***P ≤ 0.001, Student’s unpaired t test. Scale bar: 200 mm (C). Data shown are mean ± SEM and representative of 2 to 3 independent experiments. n = 8–16 mice (A); n = 3–4 mice (B–D).