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STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration

Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined...

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Autores principales: Xue, Yishu, Zhou, Yan, Bao, Wuping, Fu, Qiang, Hao, Huijuan, Han, Lei, Zhang, Xue, Tian, Xue, Zhang, Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573338/
https://www.ncbi.nlm.nih.gov/pubmed/34760922
http://dx.doi.org/10.3389/fmolb.2021.717962
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author Xue, Yishu
Zhou, Yan
Bao, Wuping
Fu, Qiang
Hao, Huijuan
Han, Lei
Zhang, Xue
Tian, Xue
Zhang, Min
author_facet Xue, Yishu
Zhou, Yan
Bao, Wuping
Fu, Qiang
Hao, Huijuan
Han, Lei
Zhang, Xue
Tian, Xue
Zhang, Min
author_sort Xue, Yishu
collection PubMed
description Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.
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spelling pubmed-85733382021-11-09 STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration Xue, Yishu Zhou, Yan Bao, Wuping Fu, Qiang Hao, Huijuan Han, Lei Zhang, Xue Tian, Xue Zhang, Min Front Mol Biosci Molecular Biosciences Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma. Frontiers Media S.A. 2021-10-25 /pmc/articles/PMC8573338/ /pubmed/34760922 http://dx.doi.org/10.3389/fmolb.2021.717962 Text en Copyright © 2021 Xue, Zhou, Bao, Fu, Hao, Han, Zhang, Tian and Zhang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Xue, Yishu
Zhou, Yan
Bao, Wuping
Fu, Qiang
Hao, Huijuan
Han, Lei
Zhang, Xue
Tian, Xue
Zhang, Min
STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
title STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
title_full STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
title_fullStr STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
title_full_unstemmed STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
title_short STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration
title_sort stat3 and il-6 contribute to corticosteroid resistance in an ova and ozone-induced asthma model with neutrophil infiltration
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573338/
https://www.ncbi.nlm.nih.gov/pubmed/34760922
http://dx.doi.org/10.3389/fmolb.2021.717962
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