Graft IL-33/ST2 signaling promotes cardiac allograft vasculopathy by modulating cardiac resident cell function.

Chronic rejection and subsequent cardiac allograft vasculopathy (CAV) remain critical challenges in transplantation. Although IL-33/ST2 signaling has been implicated in CAV progression, its precise cellular and molecular mechanisms, particularly its regulation of cardiac resident cells, remain incompletely understood. In this study, we demonstrated that graft-specific ST2 deficiency significantly attenuated allograft vasculopathy, reduced immune cell infiltration, and mitigated fibrosis. RNA sequencing revealed decreased expression of genes associated with transplant rejection, adhesion molecules and chemokines in ST2-deficient allografts. Mechanistically, IL-33 directly activated cardiac-resident endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts, driving their proliferation, dysfunction, and aberrant release of proinflammatory and profibrotic cytokines. Importantly, graft ST2 deficiency selectively attenuated the stimulating effect IL-33 on these resident cells while preserving its regulatory functions in other cell types, particularly recipient immune cells, thus reducing chronic rejection and CAV. Our findings elucidate a pivotal role for graft-specific IL-33/ST2 signaling in CAV pathogenesis and highlight its therapeutic potential as a targeted intervention.