Targeting transitioning lung monocytes/macrophages as treatment strategies in lung disease related to environmental exposures

• Published in: Respiratory research Vol. 25; no. 1; pp. 157 - 16
• Main Authors: Schwab, Aaron D, Wyatt, Todd A, Moravec, Grace, Thiele, Geoffrey M, Nelson, Amy J, Gleason, Angela, Schanze, Oliver, Duryee, Michael J, Romberger, Debra J, Mikuls, Ted R, Poole, Jill A
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.04.2024; BioMed Central; BMC
• Subjects: Acetaldehyde; Agricultural production; Analysis; Animals; Asthma; Atmospheric particulates; Bisphosphonates; Bronchus; Care and treatment; CC chemokine receptors; CD11b antigen; CD11c antigen; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Chemokines; Chronic illnesses; Chronic obstructive pulmonary disease; Citrulline; Clodronic acid; Clodronic Acid - metabolism; Clodronic Acid - pharmacology; Cloning; Collagen; Collagen - metabolism; Diagnosis; Dust; Endotoxin; Environmental Exposure; Exposure; Extracellular matrix; Fibronectin; Fibrosis; Flow cytometry; Health services; Histopathology; Immunology; Inflammation; Inhalants; Leukocytes (neutrophilic); Lipopolysaccharides - pharmacology; Liposomes; Liposomes - metabolism; Lung; Lung disease; Lung diseases; Lung Diseases - metabolism; Lungs; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Matrix metalloproteinases; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Monocytes; Monocytes - metabolism; Neutrophils; Normality; Occupational health; Organic dust; Proteins; Statistical analysis; Statistical tests; Subpopulations; Tissue inhibitor of metalloproteinases; Translation; Tumor necrosis factor-TNF; Variance analysis; Vimentin - metabolism; United States; Lung disease; Monocytes; Organic dust; Inflammation; Immunology; Endotoxin
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-024-02804-3

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. 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'smultiple comparison) and nonparametric statistical (Kruskal-Wallis, Dunn's multiple comparison) tests were used following Shapiro-Wilk testing for normality. Intratracheal instillation of ODE, LPS, or PGN robustly induced the recruitment of inflammatory CCR2 CD11c CD11b monocytes/macrophages and both CCR2 and CCR2 CD11c CD11b 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 CD11b 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 CD11b 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. Highly concentrated environmental/occupational exposures induced the recruitment of CCR2 and CCR2 transitioning monocyte-macrophage and monocyte subpopulations and targeting peripheral monocytes may reduce the adverse lung consequences resulting from exposures to LPS-enriched inhalants.