Syk from M1 macrophage exosomes drives vascular injury in kidney transplant rejection.

Antibody-mediated rejection (ABMR) remains a leading cause of renal allograft failure, characterized by peritubular capillaritis and endothelial inflammation. M1-polarized macrophages are abundantly recruited to allograft tissues during ABMR. However, the role of their secreted exosomes in vascular injury remains insufficiently defined. Here, we demonstrate that exosomes derived from M1 macrophages (M1-Exos) potently induce endothelial activation and inflammatory injury. Through transcriptomic and exosomal proteomic analyses, spleen tyrosine kinase (Syk) was identified as a protein significantly enriched in M1-Exos. Functional assays showed that M1-Exos promote the upregulation of ICAM-1, VCAM-1, and inflammatory cytokines in endothelial cells, while genetic knockdown of Syk in M1 macrophage reduced these effects. Mechanistically, exosomal Syk is transferred to endothelial cells and associates with NLRP3, driving inflammasome activation and caspase-1 cleavage. In a murine model of renal transplant, Syk-enriched exosomes aggravated endothelial injury. Meanwhile, Syk-deficient exosomes attenuated endothelial inflammation signs of ABMR in grafts. These findings identify exosomal Syk as a novel mediator of endothelial inflammation and provide insights into macrophage-endothelium communication in the setting of allograft rejection.