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Updated: May 30, 2025
Isolation and In Vitro Culture of Murine and Human Alveolar Macrophages
Published on: April 20, 2018
Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension
Rahul Kumar1,2, Kevin Nolan1, Biruk Kassa1
1Department of Medicine, University of California San Francisco, San Francisco, California, USA.
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.
Insights
Hypoxia triggers pulmonary hypertension by activating specific lung macrophages. Blocking this pathway with dexamethasone shows therapeutic potential for this vascular disease.
Area of Science:
- Pulmonary vascular disease
- Immunology
- Macrophage biology
Background:
- Hypoxia is a leading cause of pulmonary hypertension (PH).
- Interstitial pulmonary macrophages are implicated in PH pathogenesis.
- Understanding macrophage roles in hypoxic PH is crucial for developing treatments.
Purpose of the Study:
- To investigate the role of interstitial macrophages in hypoxia-induced pulmonary hypertension.
- To identify specific macrophage populations and signaling pathways involved in PH development.
- To explore potential therapeutic targets for hypoxic PH.
Main Methods:
- Utilized a hypoxia-exposed mouse model to study pulmonary hypertension.
- Analyzed macrophage populations, proliferation, and gene expression (CCL2, CCR2, thrombospondin-1).
- Investigated the effects of blocking monocyte recruitment (CCL2 antibody, CCR2 deficiency) and dexamethasone treatment.
- Examined human plasma samples from individuals ascending to high altitude.
Main Results:
- Hypoxia increased resident interstitial macrophages via proliferation and CCL2 expression.
- Recruited CCR2+ macrophages expressed thrombospondin-1, activating TGF-β and causing vascular disease.
- Blocking monocyte recruitment or CCR2 deficiency suppressed hypoxic PH.
- Human plasma showed increased thrombospondin-1 and TGF-β at high altitude, blocked by dexamethasone.
- Dexamethasone suppressed CCL2 expression and CCR2+ monocyte recruitment in mice.
Conclusions:
- A pathological crosstalk exists between two distinct interstitial macrophage populations in hypoxic PH.
- CCL2-mediated monocyte recruitment and CCR2+ macrophage activation are key drivers of vascular disease.
- Targeting this macrophage-driven pathway, potentially with dexamethasone, offers a therapeutic strategy for hypoxic PH.
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