Targeting Macrophages in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening cardiopulmonary disorder characterized by obstructive remodeling of the pulmonary vasculature, leading to increased pulmonary vascular resistance and right ventricular (RV) failure. A review published in Frontiers in Immunology in December 2025 highlights the central role of immune dysregulation, particularly macrophage biology, in PAH pathogenesis and therapeutic development. Although current treatments primarily relieve symptoms through vasodilatory effects, they do not effectively stop or reverse the underlying disease process.

Macrophages play a central role in PAH through their ability to adopt distinct functional phenotypes. M1-like macrophages drive inflammation, whereas M2-like macrophages promote tissue repair, fibrosis, and vascular remodeling. These phenotypes are shaped by factors such as hypoxia, metabolic reprogramming, and epigenetic regulation. Within the pulmonary vasculature, macrophages regulate inflammation and fibrosis via M1/M2 polarization, and their mediators can also influence systemic immunity and right ventricular remodeling through the “lung-heart immune axis.” Together, this dynamic spectrum of macrophage states drives disease progression.

Potential therapeutic approaches targeting macrophages in PAH include limiting their accumulation and activation. Inhibition of CSF1R reduces macrophage burden and improves hemodynamics, while blockade of CCR2/CCR5 signaling disrupts monocyte recruitment and macrophage-smooth muscle cell crosstalk that drives vascular remodeling. Upstream approaches, such as RUNX1 inhibition or restoration of BMPR2 signaling, further modulate macrophage activation, while targeting macrophage-derived PDGF-B addresses downstream pathways.

Targeting immunometabolism has emerged as a promising therapeutic approach. Pro-inflammatory macrophages rely on glycolysis, and inhibition of pathways such as β-catenin signaling or the glycolytic regulator PFKFB3 reduces inflammation and ameliorates pulmonary vascular remodeling in preclinical models. Additional metabolic pathways—including the pentose phosphate pathway, fatty acid oxidation, and glutamine metabolism—also modulate macrophage activation and disease progression, with some interventions improving pulmonary hemodynamics and right ventricular function. Consistent with this, hypoxia-associated regulators such as HIF-1α also represent potential therapeutic targets, as myeloid-specific HIF-1α deletion reduces macrophage infiltration and attenuates PAH severity in experimental models.

Epigenetic and inflammatory signaling pathways offer additional opportunities for intervention. Modulating RNA methylation and histone acetylation can regulate macrophage polarization and inflammatory signaling, influencing vascular remodeling and fibrosis. Targeting innate immune signaling pathways—including the stimulator of interferon genes (STING), TLR9, and the NLRP3 inflammasome—has been shown to reduce inflammation and improve outcomes in experimental models. Therapies directed at macrophage-derived mediators, including macrophage migration inhibitory factor (MIF) antagonists, as well as inhibitors of specific proteases and receptors, further demonstrate the breadth of potential intervention points.

Finally, advances in drug delivery, including engineered extracellular vesicles, nanoparticle-based systems, and receptor fusion proteins, offer the potential to more precisely target macrophage populations and modulate multiple disease pathways simultaneously.

Ultimately, macrophage-directed therapies represent a shift toward disease-modifying strategies in PAH. Future progress will depend on better defining pathogenic macrophage subsets and developing targeted interventions that balance efficacy with preservation of immune function.

Reference:

Xu W, Shen Y, Wan Z, Guo J. Macrophage-driven immunopathology in pulmonary arterial hypertension: from mechanisms to targeted therapies. Front Immunol. 2025;16:1721071. Published 2025 Dec 17. doi:10.3389/fimmu.2025.172107