M1 Macrophage is a Novel Potential Trigger for Endothelial Senescence: Role of Exosomal miR-155 Targeting SOCS1 Signal

Abstract

Age-related proinflammatory microenvironment induced by infiltration of M1 macrophages promotes endothelial senescence-mediated vascular diseases. Macrophages exert their immunomodulatory effects by releasing exosomes. However, the underlying mechanisms governing endothelial cell senescence induced by exosomes derived from M1 macrophages (M1-Exo) remain elusive. In this study, we delved into the intricate interplay between endothelial function and M1 macrophage abundance in the aortas and explored the pivotal role of M1-Exo in endothelial cell senescence and its associated molecular pathways. Our results unveiled a compelling correlation between the infiltration of M1 macrophages in the aortas of aged mice and impaired endothelium-dependent dilatation. Coculturing endothelial cells with M1-Exo engendered the acquisition of a senescent phenotype, marked by increased senescence-associated beta-galactosidase level and a distinct senescence-associated secretory profile. Endothelial cells cocultured with M1-Exo exhibited pronounced signs of cell cycle arrest, accompanied by mitochondrial oxidative damage and dysfunction. Bioinformatics analysis and subsequent validation identified high expression of miR-155 in M1-Exo. The transfer of miR-155 contributed to the prosenescence effect of M1-Exo by targeting SOCS1, subsequently activating JAK2/STAT3 signaling. The administration of M1-Exo into young mice instigated endothelial dysfunction and increased ROS production. Notably, the reduction of miR-155 in M1-Exo partially mitigated such deleterious effects. Our findings demonstrate that exosomal miR-155, originating from M1 macrophages, elicits endothelial cell senescence. The present study brings a groundbreaking insight into the communication between M1 macrophages and endothelial cells as a mediator of vascular aging, providing a promising target for interventions in age-related vascular diseases.