IL-6 Deficiency Exacerbates Allergic Asthma and Abrogates the Protective Effect of Allergic Inflammation against Streptococcus pneumoniae Pathogenesis
- 15 July 2020
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 205 (2), 469-479
- https://doi.org/10.4049/jimmunol.1900755
Abstract
Allergic asthma (AA) is characterized as a Th2-biased airway inflammation that can develop lung inflammation and remodeling of the respiratory tract. Streptococcus pneumoniae is a major respiratory pathogen, causing noninvasive (otitis media and pneumonia) and invasive diseases (sepsis) in humans. We sought to determine the role of IL-6 in the regulation of lung inflammation in murine AA caused by Aspergillus fumigatus as well as its consequence on the regulation of airway barrier integrity and S. pneumoniae disease. In an AA model, IL-6 deficiency led to increased lung inflammation, eosinophil recruitment, tissue pathology, and collagen deposition. Additionally, IL-6–deficient asthmatic mice exhibited reduced goblet cell hyperplasia and increased TGF-β production. These key changes in the lungs of IL-6–deficient asthmatic mice resulted in dysregulated tight junction proteins and increased lung permeability. Whereas the host response to AA protected against S. pneumoniae lung disease, the IL-6 deficiency abrogated the protective effect of allergic inflammation against S. pneumoniae pathogenesis. Consistent with in vivo data, IL-6 knockdown by small interfering RNA or the blockade of IL-6R signaling exacerbated the TGF-β–induced dysregulation of tight junction proteins, E-cadherin and N-cadherin expression, and STAT3 phosphorylation in MLE-12 epithelial cells. Our findings demonstrate a previously unrecognized role of host IL-6 response in the regulation of lung inflammation during AA and the control of S. pneumoniae bacterial disease. A better understanding of the interactions between lung inflammation and barrier framework could lead to the development of therapies to control asthma inflammation and preserve barrier integrity.Keywords
This publication has 55 references indexed in Scilit:
- Identification of a Functionally Distinct Truncated BDNF mRNA Splice Variant and Protein in Trachemys scripta elegansPLOS ONE, 2013
- Eosinophilic Inflammation in Allergic AsthmaFrontiers in Pharmacology, 2013
- Analysis of NLRP3 in the Development of Allergic Airway Disease in MiceThe Journal of Immunology, 2012
- Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lungMucosal Immunology, 2012
- Alveolar Epithelial Cells Undergo Epithelial-to-Mesenchymal Transition in Response to Endoplasmic Reticulum StressOnline Journal of Public Health Informatics, 2011
- TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cellsAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2011
- Macrophages: Master Regulators of Inflammation and FibrosisSeminars in Liver Disease, 2010
- Eosinophils and Th2 immunity: contemporary insightsImmunology & Cell Biology, 2010
- Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in MiceAmerican Journal of Respiratory and Critical Care Medicine, 2008
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001