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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

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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 1

SA subjects harbor more IFN-γ+ and IL-17A+CD4+ T cells in their airways compared with MMA subjects.

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SA subjects harbor more IFN-γ+ and IL-17A+CD4+ T cells in their airways ...
Representative flow plots (upper panels) of (A) IFN-γ+ and (B) IL17A+ CD4+ T cells in total BAL cells. Lower panels are graphical representations of percentages of (A) IFN-γ– and (B) IL-17A–expressing CD4+ T cells in total BAL cells obtained from the airways of SA (n = 11) and MMA (n = 9) subjects studied. (C) Concentration of indicated cytokines in culture supernatants of total unfractionated BAL cells from MMA and SA groups briefly cultured ex vivo. For IL-5 and IL-13 estimation, n = 9 and n = 14 for MMA and SA subjects, respectively; for IFN-γ and IL-17A estimation, n = 14 in each category. For IL-12p40, IL-4, and IL-9 estimation, n = 9 and n = 8 for MMA and SA subjects, respectively. (D) IFNG and IL12P40 mRNA expression in total BAL cells from MMA and SA subjects; n = 8 and n = 10 for MMA and SA, respectively. *P ≤ 0.05; ***P ≤ 0.001; NS, nonsignificant, Student’s unpaired t test or Mann-Whitney U test based on normality of data.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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