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Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension
Rahul Kumar, … , Qadar Pasha, Brian B. Graham
Rahul Kumar, … , Qadar Pasha, Brian B. Graham
Published January 30, 2025
Citation Information: J Clin Invest. 2025;135(6):e176865. https://doi.org/10.1172/JCI176865.
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Research Article Inflammation Vascular biology Article has an altmetric score of 31

Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension

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Abstract

Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment, which express the protein thrombospondin-1, which functionally activates TGF-β to cause vascular disease. Blockade of monocyte recruitment with either CCL2-neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who traveled from low (225 m) to high (3500 m) elevation, revealing an increase in thrombospondin-1 and TGF-β expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2+ monocyte recruitment. These data suggest a pathologic cross talk between 2 discrete interstitial macrophage populations, which can be therapeutically targeted.

Authors

Rahul Kumar, Kevin Nolan, Biruk Kassa, Neha Chanana, Tsering Palmo, Kavita Sharma, Kanika Singh, Claudia Mickael, Dara Fonseca Balladares, Julia Nilsson, Amit Prabhakar, Aastha Mishra, Michael H. Lee, Linda Sanders, Sushil Kumar, Ari B. Molofsky, Kurt R. Stenmark, Dean Sheppard, Rubin M. Tuder, Mohit D. Gupta, Tashi Thinlas, Qadar Pasha, Brian B. Graham

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Figure 4

Genetic and pharmacologic blockade of CCR2-CCL2 axis protects from hypoxic PH.

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Genetic and pharmacologic blockade of CCR2-CCL2 axis protects from hypox...
(A) Schematic showing the BM reconstitution of Ccr2–/– and WT BM into lethally irradiated WT mice. WT mice reconstituted with Ccr2–/– BM were protected from hypoxic PH by attenuated (B) RVSP (n = 7–11/group) and (C) RV hypertrophy (n = 7–11/group) as measured by Fulton Index, compared with WT mice that were reconstituted with WT BM. (D) Schematic showing pharmacological blockade of CCR2 ligands CCL2 or CCL7 using anti-CCL2 or anti-CCL7 neutralizing antibody treatment. Hypoxia-exposed WT mice treated with CCL2 NAb but not CCL7 NAb showed lower (E) RVSP (n = 6/group) and (F) RV hypertrophy (n = 6/group). TSP-1 levels in (G) lungs (n = 6/group) and (H) blood (n = 6/group); and TGF-β1 levels in (I) lungs (n = 6/group) and (J) blood (n = 6/group) compared with WT mice treated with isotype control antibody. Data in all panels followed a normal distribution. ANOVA with the Tukey test was performed for multiple comparisons. Data were obtained from the female mice. mean ± SD plotted. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n, number of animals; TSP-1, thrombospondin-1; TGF-β1, transforming growth factor-1; IMs, Interstitial macrophages; Ab, antibody; Nab, neutralizing antibody.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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