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

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 8

DEX prophylaxis blunts CCL2 production by resident IMs and blocks the recruitment of TSP-1–producing CCR2+ IMs in hypoxia.

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DEX prophylaxis blunts CCL2 production by resident IMs and blocks the re...
(A) DEX prophylactically treated, hypoxia-exposed Ccl2RFP–fl reporter mice exhibited a significant reduction in CCL2+ IMs, particularly in (B) CCL2RFP+ resident IMs (n = 7/group). Additionally, (C) intracellular CCL2 flow cytometry analysis in DEX prophylactically treated hypoxia-exposed WT mice revealed a decrease in CCL2 expressing FOLR2+ resident IMs (n = 7/group, female mice). (D) qPCR on flow-sorted FOLR+ IM from DEX-prophylactically treated hypoxia-exposed WT mice showed lower Ccl2 expression. (E) DEX prophylaxis attenuated the TSP-1 expressing CCR2+ IMs in hypoxia (n = 7/group, female mice). (F) qPCR on flow-sorted CCR2+ IM from DEX prophylactically treated hypoxia-exposed WT mice showed lower Thbs1 expression (n = 5/group, female mice). (G) Double-reporter mice displayed a marked reduction in RFP+ IMs and resident IMs in the hypoxia-exposed DEX prophylatically treated group (n = 9/group; 4 female, 5 male in vehicle; 5 female, 4 male in DEX group). Moreover, DEX prophylaxis further decreased (H) total IMs (n = 7/group, female mice) by abrogating the recruitment of (I) CCR2+ IMs and reducing the number of FOLR2+ IMs (n = 7/group, female mice) via (J) blocking proliferation, as indicated by Ki-67 expression (n = 7–13/group, female mice). Statistical analysis was conducted using ANOVA, followed by Tukey’s post hoc test for all the panels except panel J. Kruskal-Wallis ANOVA followed by Dunn’s post hoc test was used for panel J. mean ± SD plotted. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.