Mesenchymal IL-33 licenses reparative macrophages to facilitate endovascular injury-induced neointimal hyperplasia [RNA-Seq]

Immune remodeling is crucial for tissue repair, but the interaction between arterial macrophages and mesenchymal stromal cells (MSCs) in neointimal hyperplasia is not well understood. Herein, we identified Il33-expressing MSCs serve as the key regulators of arterial immune responses following endovascular injury via facilitating the recruitment of reparative macrophages. Using temporal-resolving scRNA-seq and multi-color flow cytometry, we revealed a distinct subset of LY6C-CD63+CD72+ reparative macrophages essential for vascular smooth muscle cell (VSMC) proliferation and neointimal formation. These ST2-expressing macrophages are recruited and activated by MSC-derived IL-33, which is upregulated via NFκB signaling following injury, and in turn amplify the osteopontin (OPN) production that drives VSMC proliferation. Furthermore, hydrogel-mediated local delivery of siRNAs targeting Il33 or Spp1 reduced neointimal hyperplasia, confirming the importance of the IL-33-ST2-OPN axis in pathological vascular remodeling. Our findings uncover a critical role of mesenchymal IL-33 in orchestrating immune cell recruitment and promoting VSMC proliferation, suggesting that targeting this pathway may offer therapeutic potential for preventing restenosis and other vascular diseases.