Targeting colony-stimulating factor-1 receptor attenuates the development of pulmonary arterial hypertension through C-C motif chemokine ligand 2

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressure and right ventricular failure. The perivascular macrophages in the lungs play a crucial role in the development of PAH. Here, we tested the hypothesis that colony-stimulating factor 1 receptor (CSF1R), essential for macrophage proliferation and polarization, contributed to the progression of PAH, and targeting CSF1R could offer a potential therapeutic strategy. In the lungs of patients with PAH, we found that the number of perivascular CSF1R-positive macrophages and M2 macrophages significantly increased. In the experimental sugen/hypoxia-induced PAH model, knockdown of CSF1R in the lungs decreased right ventricular systolic pressure and the number of perivascular macrophages. Pharmacological inhibition with a CSF1R inhibitor, pexidartinib, and anti-CSF1R neutralizing antibody blocked perivascular macrophage accumulation and improved the severity of pulmonary hypertension in the murine PAH models. Mechanistically, C-C motif chemokine ligand 2 (CCL2) produced by M2 macrophages was identified as a key driver for pulmonary artery smooth muscle cell proliferation, leading to pulmonary arterial remodeling. Activation of CSF1R and c-Jun N terminal kinase (JNK) transcriptionally regulated <i>Ccl2</i> expressions in macrophages. In conclusion, our study suggests that CSF1R and M2 macrophages have critical roles in the progression of PAH through CCL2.