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Updated: Jan 7, 2026
Proteomic Analysis of Human Macrophage Polarization Under a Low Oxygen Environment
Published on: January 7, 2019
Differential Impact of Recruited and Resident Macrophages on Hypoxia-Induced Pulmonary Hypertension
Shumin Guo1, Ting Pan1, Xiaojie Yan2
1Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology (S.G., T.P., Y.C., R.D., Q.L., Y. Zhuo, Y. Zhao, D.T., X.S., T.Q., X.C., D.H., Y.S., Y.Y.), School of Basic Medical Sciences, Tianjin Medical University, China.
Background:
Pulmonary interstitial macrophages can be divided into 2 distinct subsets with different origins: resident macrophages (resMФs) and recruited macrophages (recMФs). However, their specific roles in pulmonary arterial hypertension remain unclear.
Methods:
Bone marrow transplantation, the DT (diphtheria toxin) receptor system, and genetically modified murine models were utilized to explore how key TFs (transcription factors) regulate phenotype alterations in pulmonary resMФs and recMФs in an SU5416/hypoxia murine model of pulmonary hypertension (PH). Therapeutic approaches included DNA aptamer-based proteolysis-targeting chimera and small interfering RNA-loaded lipid nanoparticle for treating SU5416/hypoxia-exposed rats.
Results:
Depletion of either resMФs or recMФs using DT treatment significantly reduced SU5416/hypoxia-induced PH in mice. Pulmonary recMФs exhibited a proinflammatory phenotype during PH, driven by the TF Hic1 (hypermethylated in cancer 1). Bone marrow transplantation with Hic1-/- recMФs ameliorated PH in mice. Hic1 enhanced proinflammatory gene transcription by inhibiting Sirt1 (sirtuin 1)-mediated H3K9ac (histone H3 lysine 9 acetylation) deacetylation in the promoter regions. In contrast, pulmonary resMФs demonstrated a profibrotic transcriptome characterized by upregulation of MMP genes that are, in turn, regulated by Prrx2 (paired-related homeobox 2). Prrx2 deletion in resMФs protected against PH in mice by reducing perivascular fibrosis. Simultaneously targeting Prrx2 and Hic1 in macrophages significantly alleviated SU5416/hypoxia-induced PH in rats.
Conclusions:
The differential roles of pulmonary resMФs and recMФs in pulmonary vascular remodeling highlight novel therapeutic targets for pulmonary arterial hypertension treatment, specifically through inhibition of Hic1 and Prrx2 in macrophages.
Insights
Pulmonary arterial hypertension (PAH) involves two macrophage types: resident and recruited. Targeting Hic1 in recruited macrophages and Prrx2 in resident macrophages offers novel therapeutic strategies for PAH.
Area of Science:
- Pulmonary vascular remodeling
- Macrophage biology
- Pulmonary arterial hypertension
Background:
- Pulmonary interstitial macrophages comprise distinct resident (resMФs) and recruited (recMФs) subsets with unclear roles in pulmonary arterial hypertension (PAH).
- Understanding the specific functions of these macrophage subsets is crucial for developing targeted PAH therapies.
Purpose of the Study:
- To elucidate the distinct roles of resMФs and recMФs in the pathogenesis of pulmonary hypertension (PH).
- To identify key transcription factors regulating macrophage phenotypes in PH.
- To evaluate novel therapeutic strategies targeting these macrophage subsets in preclinical models of PH.
Main Methods:
- Utilized bone marrow transplantation, diphtheria toxin (DT) receptor system, and genetically modified murine models to study macrophage phenotypes in an SU5416/hypoxia-induced PH model.
- Employed DNA aptamer-based proteolysis-targeting chimera and small interfering RNA-loaded lipid nanoparticles for therapeutic interventions in rats.
Main Results:
- Depletion of either resMФs or recMФs significantly reduced PH severity in mice.
- Pulmonary recMФs exhibited a proinflammatory phenotype driven by the transcription factor Hic1 (hypermethylated in cancer 1), and Hic1 deficiency ameliorated PH.
- Pulmonary resMФs displayed a profibrotic transcriptome regulated by Prrx2 (paired-related homeobox 2), with Prrx2 deletion protecting against PH by reducing fibrosis. Simultaneous targeting of Hic1 and Prrx2 alleviated PH in rats.
Conclusions:
- Pulmonary resMФs and recMФs play differential roles in pulmonary vascular remodeling during PAH.
- Inhibition of Hic1 in recMФs and Prrx2 in resMФs represents promising therapeutic targets for PAH treatment.
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