MHCIILYVE1CCR2 Interstitial Macrophages Promote Medial Fibrosis in Pulmonary Arterioles and Contribute to Pulmonary Hypertension.

BACKGROUND

Pulmonary hypertension (PH) is a lethal disease characterized in part by progressive pulmonary arteriole (PA) remodeling. Excessive PA fibrosis and macrophage infiltration are often present in PH, but the potential associations are obscure. We investigated the link between interstitial macrophage (iMΦ) infiltration and PA fibrosis in PH and idiopathic pulmonary arterial hypertension.

METHODS

Lung tissue samples from patients with idiopathic pulmonary arterial hypertension and experimental PH animals were obtained to analyze the extent of fibrosis and iMΦ infiltration in the different layers of PAs and their correlation with disease severity. Single-cell RNA sequencing, lineage tracing, histological analyses, iMΦ and PA smooth muscle cell coculture, and transgenic animal experiments were used to investigate the cell heterogeneity and origins and molecular mechanisms by which iMΦs promote PA fibrosis.

RESULTS

We found that increased collagen deposition and fibrosis in the PA media were most strongly related to the severity of PH, and medial iMΦ infiltration may be involved in these pathological processes. Single-cell transcriptomics revealed that major histocompatibility complex class II (high) lymphatic vessel endothelial hyaluronan receptor 1 (low) C-C motif chemokine receptor 2 (high) (MHCIILYVE1CCR2) iMΦs were the major type of iMΦ that expanded upon Sugen-5416 and hypoxia plus normoxia stimulation and were responsible for PA medial fibrosis. Lineage tracing experiments suggested that these medial iMΦs were largely from recruited monocytes. Mechanistically, MHCIILYVE1CCR2 iMΦs promoted the transition of PA smooth muscle cells to a fibroblast-like phenotype through the WNT11 (wingless member 11)/planar cell polarity (PCP) pathway. deletion in iMΦs from PH rats normalized the fibrotic PA smooth muscle cell phenotype and decreased PA medial fibrosis, thereby improving vascular compliance and protecting against PH. Moreover, myeloid-specific deficiency in PH-PAs inhibited the medial infiltration of MHCIILYVE1CCR2 iMΦs, which also relieved PH.

CONCLUSIONS

This study demonstrates that the recruitment of MHCIILYVE1CCR2 iMΦs leads to medial fibrosis in PH-PAs associated with PH severity and that inhibition of their pathogenicity or recruitment reverses PA medial fibrosis and PH.