Differential Impact of Recruited and Resident Macrophages on Hypoxia-Induced Pulmonary Hypertension

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.