ArticleJournal of immunology (Baltimore, Md. : 1950)2014
Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension.
Article in Journal of immunology (Baltimore, Md. : 1950), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers, 1 of them a synthesis that pooled it.
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Who cites it
149 citing papers in PubMed, 1 synthesis or guideline pooled it, 246 citations in OpenAlex.
- Meta-analysis of blood genome-wide expression profiling studies in pulmonary arterial hypertension.American journal of physiology. Lung cellular and molecular physiology · 2020Pooled it
- Safety and Efficacy of Immunoadsorption as an Add-On to Medical Treatment in Patients with Severe Idiopathic Pulmonary Arterial Hypertension.Respiration; international review of thoracic diseases · 2017Trial
- Interleukin-6 is critical in the development of pulmonary vascular disease inProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Article
- Decoding spatial transcriptomics across multicellular and subcellular resolutions.Nature communications · 2026Article
- C/EBPγ interacts with C/EBPα and activates the β-catenin pathway in idiopathic pulmonary fibrosis.Cellular and molecular life sciences : CMLS · 2026Article
- From nanotechnology to immunomodulation: emerging strategies targeting macrophages in high altitude pulmonary hypertension.Journal of nanobiotechnology · 2026Review
- Adventitial Niches, Complement and Inflammation in Pulmonary Vascular Disease: Current Status and Future Directions.Comprehensive Physiology · 2026Review
- Single-cell and spatial profiling highlights TB-induced myofibroblasts as drivers of lung pathology.The Journal of experimental medicine · 2026Article
- The hypoxic tight-skin mouse model of Group 3 pulmonary hypertension.Scientific reports · 2026Article
- Interferon receptor gene dosage differentially regulates hypoxia-induced platelet activation and pulmonary hypertension in down syndrome.Frontiers in immunology · 2026Article
- Retinal microvascular and neuroretinal structural changes in pulmonary arterial hypertension assessed by OCTA: a comparative study.Turkish journal of medical sciences · 2026Article
- A Lifelong Journey in the Field of the Pulmonary Circulation: Perspectives Through the Lens of the Cardiovascular Pulmonary Research Laboratory.Pulmonary circulation · 2025Article
- Effect of Fibroblast Signaling on Macrophage Polarization.The American journal of pathology · 2025Article
- Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025Review
- Vascular EC-SOD limits the accumulation, proinflammatory profibrotic reprogramming, and hyaluronan binding of interstitial macrophages in hypoxia.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Molecular Pathogenesis of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: A Narrative Review.Biomolecules · 2025Review
- Altered maturation and activation state of circulating monocytes is associated with their enhanced recruitment in pulmonary arterial hypertension.Respiratory research · 2025Article
- When cell teamwork turns toxic.eLife · 2025Article
- Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease.eLife · 2025Article
89 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 2 institutions in 2 countries.
Funding
Abstract
Macrophage accumulation is not only a characteristic hallmark but is also a critical component of pulmonary artery remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Using multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, and primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive pulmonary arteries (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL-6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL-4/IL-13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation, complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, and deficiency in C/EBPβ or HIF1 attenuated fibroblast-driven macrophage activation. These findings challenge the current paradigm of IL-4/IL-13-STAT6-mediated alternative macrophage activation as the sole driver of vascular remodeling in PH, and uncover a cross-talk between adventitial fibroblasts and macrophages in which paracrine IL-6-activated STAT3, HIF1α, and C/EBPβ signaling are critical for macrophage activation and polarization. Thus, targeting IL-6 signaling in macrophages by completely inhibiting C/EBPβ or HIF1α or by partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL-6 and absent IL-4/IL-13 signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.