Importantly, further studies that explore alternative CCL2 sources and alternative stimuli beyond hypoxia that contribute to hypoxia-related PH are worth pursuing. The source of CCL2 production in response to hypoxia is most likely not restricted to interstitial macrophages of the lung. Hypoxia-stimulated CCL2 could very well be expressed by interstitial macrophages within other organs such as the brain and the intestine, and/or by other cell types such as endothelial cells, fibroblasts, smooth muscle cells, or adipocytes. While Kumar and colleagues have performed a multiorgan assessment of CCL2 expression in the heart, kidney, liver and spleen, CCL2 expression, in particular, in the intestine was not reported. The concept of a lung-gut axis in the context of hypoxia is explored in several studies (12). For instance, a review titled “The Bidirectional Gut-Lung Axis in Chronic Obstructive Pulmonary Disease” discusses how systemic hypoxia and oxidative stress in COPD may influence intestinal dysfunction, highlighting the role of the gut-lung axis in disease progression (13). Furthermore, blocking CCR2/CCL2 signaling only partially abrogated the PH phenotype, suggesting that parallel mechanisms, potentially involving other signaling pathways or other immune cells, contribute to hypoxic PH.

Other interesting questions and future directions include: (a) Addressing whether this paradigm of monocyte migration through CCL2/CCR2 signaling also plays a role in other forms of pulmonary hypertension, especially given that TGF-β–mediated vascular remodeling is known to be involved in Group 1 PAH. Additionally, therapeutic treatment with ActRIIA-Fc, a ligand trap for ligands of the TGF-β superfamily, has been shown to reverse proinflammatory and proliferative gene expression profiles and to normalize macrophage infiltration in diseased rodent lungs (14). Could ActRIIA-Fc also protect against hypoxia-induced PH, in mouse model and patients with Group 3 PH? (b) Recent single-cell RNA-seq (scRNA-seq) studies on lung tissue from patients with Scleroderma-associated PAH (SSc-PAH), idiopathic PAH (IPAH), and healthy donor controls using ligand-receptor signaling pairing revealed macrophage-to-endothelial cell signaling, especially in SSc-PAH compared to IPAH (15). Future scRNAseq studies in hypoxic PH could enhance our understanding of cell-cell interactions, helping to explain why certain macrophage populations accumulate in specific lung areas — primarily around pulmonary arteries as opposed to systemic arteries or pulmonary veins — and to which cells they signal. These studies could, therefore, uncover the signaling networks between various immune cells and vascular cells involved in the remodeling process with the goal to inhibit specific pathways for therapeutic purposes.

In conclusion, the interaction between different interstitial macrophage populations in the lung plays a crucial role in perivascular inflammation and vascular remodeling in hypoxia-induced PH. Understanding the macrophage dynamics and signaling pathways involved is important to develop effective treatment strategies for managing hypoxic PH, and the study by Kumar et al. presents a substantial step forward.