Abstract Body: Background: Phagocytic clearance of dying cells by efferocytosis is pivotal for the inflammation resolution and heart repair after myocardial infarction (MI). Macrophages are considered key phagocytes involved in efferocytosis, however, the molecular mechanisms underlying macrophage efferocytosis during MI remain vastly unknown. Here, we aimed to identify the role of mechanosensor Piezo1 in macrophage efferocytosis during MI.
Methods: Myeloid cell-specific Piezo1 deficient mice (Piezo1^ΔLyz2) and their littermate controls (Piezo1^fl/fl) underwent MI or sham operation to investigate whether Piezo1 in macrophages plays a functional role during ventricular remodeling. Bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PMs) were utilized to perform efferocytosis assays with or without Piezo1 activator Yoda1. RNA sequencing (RNA-seq) analysis was used to explore the possible molecular mechanisms.
Results: Piezo1 expression was significantly increased in BMDMs isolated from mice 3 days after MI compared to sham groups. Moreover, double immunofluorescent staining indicated that Piezo1 was more likely to colocalize with macrophages in the infarcted area 1 week post-MI. Piezo1^ΔLyz2 mice exhibited significant ameliorations in left ventricular remodeling and function after MI, accompanied with the less accumulation of apoptotic cardiomyocytes and an increased index of in vivo efferocytosis in the border area. We also found the enhanced uptake of apoptotic cells by Piezo1^ΔLyz2 mice derived BMDMs compared with Piezo1^fl/fl control. Furthermore, Piezo1 activation by Yoda1 induced defective efferocytosis in BMDMs and PMs. RNA-seq analysis revealed that Yoda1 significantly increased the mRNA level of solute carrier family 7a member 11 (SLC7A11), a negative regulator of efferocytosis. SLC7A11 knockdown in BMDMs by siRNA effectively restored the defective efferocytosis induced by Piezo1 activation. Finally, we identified that Piezo1 activation induced SLC7A11 upregulation in macrophage through a Ca²⁺/ATF4 dependent manner.
Conclusions: Taken together, our results demonstrated a novel mechanism by which Piezo1 activation impairs macrophage efferocytosis ability and results in excessive cardiomyocyte death after MI, providing a previously unknown insight into Piezo1-mediated mechanotransduction in the regulation of macrophage efferocytosis.