Zawia, A., Arnold, N.D. orcid.org/0000-0002-4317-5738, West, L. orcid.org/0000-0003-2953-2521 et al. (9 more authors) (2021) Altered macrophage polarization induces experimental pulmonary hypertension and is observed in patients with pulmonary arterial hypertension. Arteriosclerosis, thrombosis, and vascular biology, 41 (1). pp. 430-445. ISSN 1079-5642
Abstract
Objective:
To determine whether global reduction of CD68 (cluster of differentiation) macrophages impacts the development of experimental pulmonary arterial hypertension (PAH) and whether this reduction affects the balance of pro- and anti-inflammatory macrophages within the lung. Additionally, to determine whether there is evidence of an altered macrophage polarization in patients with PAH.
Approach and Results:
Macrophage reduction was induced in mice via doxycycline-induced CD68-driven cytotoxic diphtheria toxin A chain expression (macrophage low [MacLow] mice). Chimeric mice were generated using bone marrow transplant. Mice were phenotyped for PAH by echocardiography and closed chest cardiac catheterization. Murine macrophage phenotyping was performed on lungs, bone marrow–derived macrophages, and alveolar macrophages using immunohistochemical and flow cytometry. Monocyte-derived macrophages were isolated from PAH patients and healthy volunteers and polarization capacity assessed morphologically and by flow cytometry. After 6 weeks of macrophage depletion, male but not female MacLow mice developed PAH. Chimeric mice demonstrated a requirement for both MacLow bone marrow and MacLow recipient mice to cause PAH. Immunohistochemical analysis of lung sections demonstrated imbalance in M1/M2 ratio in male MacLow mice only, suggesting that this imbalance may drive the PAH phenotype. M1/M2 imbalance was also seen in male MacLow bone marrow–derived macrophages and PAH patient monocyte-derived macrophages following stimulation with doxycycline and IL (interleukin)-4, respectively. Furthermore, MacLow-derived alveolar macrophages showed characteristic differences in terms of their polarization and expression of diphtheria toxin A chain following stimulation with doxycycline.
Conclusions:
These data further highlight a sex imbalance in PAH and further implicate immune cells into this paradigm. Targeting imbalance of macrophage population may offer a future therapeutic option.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, (http://creativecommons.org/licenses/by-nc/4.0/) which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes. |
Keywords: | Muscle, Smooth, Vascular; Pulmonary Artery; Macrophages, Alveolar; Myocytes, Smooth Muscle; Animals; Mice, Transgenic; Humans; Disease Models, Animal; Diphtheria Toxin; Peptide Fragments; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Case-Control Studies; Sex Factors; Paracrine Communication; Cell Proliferation; Macrophage Activation; Phenotype; Adult; Aged; Middle Aged; Female; Male; Vascular Remodeling; Hypoxia; Pulmonary Arterial Hypertension |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number British Heart Foundation BHF-FS/18/52/33808 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 30 Mar 2021 15:52 |
Last Modified: | 01 Apr 2021 04:50 |
Status: | Published |
Publisher: | Wolters Kluwer Health |
Refereed: | Yes |
Identification Number: | 10.1161/atvbaha.120.314639 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:172643 |