Tolerogenic signaling of alveolar macrophages induces lung adaptation to oxidative injury.

Abstract

BACKGROUND:

Inhaled oxidative toxicants present in ambient air cause airway epithelial injury, inflammation, and airway hyperresponsiveness. Effective adaptation to such environmental insults is essential for the preservation of pulmonary function, whereas failure or incomplete adaptation to oxidative injury can render the host susceptible to the development of airway disease.

OBJECTIVE:

We sought to explore the mechanisms of airway adaptation to oxidative injury.

METHODS:

For a model to study pulmonary adaptation to oxidative stress-induced lung injury, we exposed mice to repeated nose-only chlorine gas exposures. Outcome measures were evaluated 24 hours after the last chlorine exposure. Lung mechanics and airway responsiveness to methacholine were assessed by using the flexiVent. Inflammation and antioxidant responses were assessed in both bronchoalveolar lavage fluid and lung tissue. Using both loss or gain of function and genomic approaches, we further dissected the cellular and molecular mechanisms involved in pulmonary adaptation.

RESULTS:

Repeated exposures to oxidative stress resulted in pulmonary adaptation evidenced by abrogation of neutrophilic inflammation and airway hyperresponsiveness. This adaptation was independent of antioxidant mechanisms and regulatory T cells but dependent on residential alveolar macrophages (AMs). Interestingly, 5% of AMs expressed forkhead box P3, and depletion of these cells abolished adaptation. Results from transcriptomic profiling and loss and gain of function suggest that adaptation might be dependent on TGF-β and prostaglandin E2.

CONCLUSION:

Pulmonary adaptation during oxidative stress-induced lung injury is mediated by a novel subset of forkhead box P3-positive AMs that limits inflammation, favoring airway adaptation and host fitness through TGF-β and prostaglandin E2.

• Authors: Benoit Allard, Alice Panariti, Erwan Pernet, Jeffrey Downey, Satoshi Ano, Marieme Dembele, Emily Nakada, Utako Fujii, Toby K McGovern, William S Powell, Maziar Divangahi, James G Martin
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 144 Issue 4 Pg. 945-961.e9 (10 2019) ISSN: 1097-6825 [Electronic] United States
• PMID: 31356919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Irritants
• Transforming Growth Factor beta
• Chlorine
• Dinoprostone

Topics

• Adaptation, Physiological (physiology)
• Animals
• Chlorine (toxicity)
• Dinoprostone (metabolism)
• Inflammation (chemically induced, immunology, metabolism)
• Irritants (toxicity)
• Lung Injury (chemically induced, immunology, metabolism)
• Macrophages, Alveolar (immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Oxidative Stress (drug effects, immunology)
• Respiratory Hypersensitivity (chemically induced, immunology, metabolism)
• Transforming Growth Factor beta (metabolism)