Targeting Transitioning Lung Monocytes/Macrophages as Treatment Strategies in Lung Disease Related to Environmental Exposures

Authors

Aaron Schwab, University of Nebraska Medical CenterFollow
Todd A. Wyatt, twyatt@unmc.eduFollow
Grace Moravec, University of Nebraska Medical Center
Geoffrey M. Thiele, University of Nebraska Medical CenterFollow
Amy J. Nelson, University of Nebraska Medical CenterFollow
Angela Gleason, University of Nebraska Medical CenterFollow
Oliver Schanze, University of Nebraska Medical CenterFollow
Michael J. Duryee, University of Nebraska Medical CenterFollow
Debra J. Romberger, University of Nebraska Medical CenterFollow
Ted R. Mikuls, University of Nebraska Medical CenterFollow
Jill A. Poole, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Respiratory Research

Publication Date

2024

Volume

25

Abstract

Background: Environmental/occupational exposures cause significant lung diseases. Agricultural organic dust extracts (ODE) and bacterial component lipopolysaccharide (LPS) induce recruited,transitioning murine lung monocytes/macrophages, yet their cellular role remains unclear.

Methods: CCR2 RFP⁺ mice were intratracheally instilled with high concentration ODE (25%), LPS (10 μg), or gram-positive peptidoglycan (PGN, 100 μg) for monocyte/macrophage cell-trafficking studies. CCR2 knockout (KO) mice and administration of intravenous clodronate liposomes strategies were employed to reduce circulating monocytes available for lung recruitment following LPS exposure.Lung tissues and bronchoalveolar lavage fluid (BALF) were collected. Pro-inflammatory and/or pro-fibrotic cytokines, chemokines, and lung extracellular matrix mediators were quantitated by ELISA. Infiltrating lung cells including monocyte/macrophage subpopulations, neutrophils, and lymphocytes were characterized by flow cytometry.Lung histopathology, collagen content, vimentin, and post-translational protein citrullination and malondialdehyde acetaldehyde (MAA) modification were quantitated. Parametric statistical tests (one-way ANOVA, Tukey's multiple comparison) and nonparametric statistical (Kruskal-Wallis, Dunn's multiple comparison) tests were used following Shapiro-Wilk testing for normality.

Results: Intratracheal instillation of ODE, LPS, or PGN robustly induced the recruitment of inflammatory CCR2⁺ CD11c^intCD11b^hi monocytes/macrophages and both CCR2⁺ and CCR2^- CD11c^-CD11b^hi monocytes at 48 h. There were also increases in CCR2⁺ CD4⁺ and CD8⁺ T cells and NK cells. Despite reductions in LPS-induced lung infiltrating CD11c^intCD11b^hi cells (54% reduction), CCR2 knockout (KO) mice were not protected against LPS-induced inflammatory and pro-fibrotic consequences. Instead, compensatory increases in lung neutrophils and CCL2 and CCL7 release occurred. In contrast, the depletion of circulating monocytes through the administration of intravenous clodronate (vs. vehicle) liposomes 24 h prior to LPS exposure reduced LPS-induced infiltrating CD11c^intCD11b^hi monocyte-macrophage subpopulation by 59% without compensatory changes in other cell populations. Clodronate liposome pre-treatment significantly reduced LPS-induced IL-6 (66% reduction), matrix metalloproteinases (MMP)-3 (36%), MMP-8 (57%), tissue inhibitor of metalloproteinases (61%), fibronectin (38%), collagen content (22%), and vimentin (40%). LPS-induced lung protein citrullination and MAA modification, post-translational modifications implicated in lung disease, were reduced (39% and 48%) with clodronate vs. vehicle liposome.

Conclusion: Highly concentrated environmental/occupational exposures induced the recruitment of CCR2⁺ and CCR2^-transitioning monocyte-macrophage and monocyte subpopulations and targeting peripheralmonocytes may reduce the adverse lung consequences resulting from exposures to LPS-enriched inhalants.

MeSH Headings

Mice, Animals, Monocytes, Liposomes, Vimentin, Lipopolysaccharides, Clodronic Acid, CD8-Positive T-Lymphocytes, Lung, Macrophages, Lung Diseases, Environmental Exposure, Collagen, Mice, Inbred C57BL

DOI Link

10.1186/s12931-024-02804-3

ISSN

1465-993X

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Schwab, Aaron; Wyatt, Todd A.; Moravec, Grace; Thiele, Geoffrey M.; Nelson, Amy J.; Gleason, Angela; Schanze, Oliver; Duryee, Michael J.; Romberger, Debra J.; Mikuls, Ted R.; and Poole, Jill A., "Targeting Transitioning Lung Monocytes/Macrophages as Treatment Strategies in Lung Disease Related to Environmental Exposures" (2024). Journal Articles: Pulmonary & Critical Care Med. 17.
https://digitalcommons.unmc.edu/com_pulm_articles/17