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Citations to this article

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.
View: Text | PDF | Corrigendum
Research Article Pulmonology Article has an altmetric score of 25

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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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 Total
Citations: 21 29 32 26 34 17 13 12 24 14 2 224
Citation information
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Citations to this article in year 2018 (12)

Title and authors Publication Year
Mast cells as sources of cytokines, chemokines, and growth factors
K Mukai, M Tsai, H Saito, SJ Galli
Immunological Reviews 2018
T H 1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status
JA Wisniewski, LM Muehling, JD Eccles, BJ Capaldo, R Agrawal, DA Shirley, JT Patrie, LJ Workman, AJ Schuyler, MG Lawrence, WG Teague, JA Woodfolk
Journal of Allergy and Clinical Immunology 2018
Updates on T helper type 17 immunity in respiratory disease
N Iwanaga, JK Kolls
Immunology 2018
T cells in severe childhood asthma
AG Paul, LM Muehling, JD Eccles, JA Woodfolk
Cell 2018
IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma
NR Bhakta, SA Christenson, S Nerella, OD Solberg, CP Nguyen, DF Choy, KL Jung, S Garudadri, LR Bonser, JL Pollack, LT Zlock, DJ Erle, C Langelier, JL Derisi, JR Arron, JV Fahy, PG Woodruff
American journal of respiratory and critical care medicine 2018
Puerarin alleviates delayed-type hypersensitivity via cytokine inhibition by modulating Th1/Th2 balance
J Tong, XJ Hu, WQ Cai, X Dai, L Wang
Experimental and therapeutic medicine 2018
Hormones, sex, and asthma
JA Yung, H Fuseini, DC Newcomb
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2018
Rhinovirus infection induces distinct transcriptome profiles in polarized human macrophages
C Rajput, MP Walsh, BN Eder, EE Metitiri, AP Popova, MB Hershenson
Physiological genomics 2018
IFN-stimulated Genes and Non–Type 2 Inflammation. New Pathway or Red Herring?
S Sharma, F Holguin
American journal of respiratory and critical care medicine 2018
Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease
ME Kuruvilla, FE Lee, GB Lee
Clinical Reviews in Allergy & Immunology 2018
Influence of viral infection on the relationships between airway cytokines and lung function in asthmatic children
TC Lewis, EE Metitiri, GB Mentz, X Ren, AR Carpenter, AM Goldsmith, KE Wicklund, BN Eder, AT Comstock, JM Ricci, SR Brennan, GL Washington, KB Owens, B Mukherjee, TG Robins, SA Batterman, MB Hershenson
Respiratory Research 2018
Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis
CC Campa, RL Silva, JP Margaria, T Pirali, MS Mattos, LR Kraemer, DC Reis, G Grosa, F Copperi, EM Dalmarco, RC Lima-Júnior, S Aprile, V Sala, FD Bello, DS Prado, JC Alves-Filho, C Medana, GD Cassali, GC Tron, MM Teixeira, E Ciraolo, RC Russo, E Hirsch
Nature Communications 2018

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