Lung Disease in Relation to Unique Monocyte-Macrophage Subpopulations Induced by Combined Inhalant Endotoxin and Collagen-Induced Arthritis

Authors

Jill A. Poole, University of Nebraska Medical CenterFollow
Aaron Schwab, University of Nebraska Medical CenterFollow
Geoffrey M. Thiele, University of Nebraska Medical CenterFollow
Todd A. Wyatt, University of Nebraska Medical CenterFollow
Amy J. Nelson, University of Nebraska Medical CenterFollow
Oliver Schanze, University of Nebraska Medical CenterFollow
Angela Gleason, University of Nebraska Medical CenterFollow
Michael J. Duryee, University of Nebraska Medical CenterFollow
Bryant England, University of Nebraska Medical CenterFollow
Ted R. Mikuls, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Frontiers in Immunology

Publication Date

2025

Volume

16

Abstract

BACKGROUND: Lung disease is the most overrepresented cause of death in rheumatoid arthritis (RA). Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA), a model that recapitulates features of RA-associated interstitial lung disease (RA-ILD). As patients with RA-ILD demonstrate unique circulating monocyte subpopulations, this study aims to characterize lung infiltrating monocytes/macrophages in a mouse model of RA-ILD and determine whether reducing these cells mitigates the development of lung disease.

METHODS: Autoimmune-prone DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for up to 5 weeks and CIA induction. Experimental groups included Sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS), and CIA+LPS (CIA/LPS). Lung disease was assessed by longitudinal imaging, lung function measurements, bronchoalveolar lavage fluid, lung tissues, and lung histopathology. Cell subpopulations were analyzed by single cell RNA-sequencing and flow cytometry. Intravenous clodronate liposome administration was employed to reduce circulating monocytes.

RESULTS: Longitudinal imaging demonstrated increased lung volume and tissue density in CIA+LPS mice. Lung function assessment showed reduced compliance and increased airway resistance with dual exposure. Unsupervised clustering revealed 16 discrete clusters among the experimental groups with robust clusters of monocytes/macrophages of overlapping characteristics for both CIA+LPS and CIA. By flow cytometry, dual CIA+LPS exposure induced activated CD11c

CONCLUSION: The interaction of inhalation-induced airway inflammation and autoimmune arthritis results in lung disease associated with uniquely activated infiltrating inflammatory interstitial macrophages. Moreover, depletion of circulating monocytes attenuated lung disease. Whereas the induced interstitial macrophage immunophenotype is more aligned to CIA than endotoxin exposure, co-exposure modeling renders unique features that potentially inform the pathogenesis and treatment of RA-ILD.

MeSH Headings

Animals, Mice, Arthritis, Experimental, Monocytes, Mice, Inbred DBA, Lipopolysaccharides, Disease Models, Animal, Male, Macrophages, Lung, Arthritis, Rheumatoid, Endotoxins, Clodronic Acid, Lung Diseases, Interstitial

DOI Link

10.3389/fimmu.2025.1557583

ISSN

1664-3224

Creative Commons License

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

Recommended Citation

Poole, Jill A.; Schwab, Aaron; Thiele, Geoffrey M.; Wyatt, Todd A.; Nelson, Amy J.; Schanze, Oliver; Gleason, Angela; Duryee, Michael J.; England, Bryant; and Mikuls, Ted R., "Lung Disease in Relation to Unique Monocyte-Macrophage Subpopulations Induced by Combined Inhalant Endotoxin and Collagen-Induced Arthritis" (2025). Journal Articles: Environmental, Agricultural & Occupational Health. 23.
https://digitalcommons.unmc.edu/coph_env_articles/23