Cardiomyocytic cyclic GMP-AMP synthase is critical for the induction of experimental cardiac graft rejection

Objective During cardiac transplantation, cellular injury and DNA damage can result in the accumulation of cytosolic double-stranded DNA (dsDNA), which can activate the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling pathway and thus induce multiple proinflammatory responses. However, the role of the cGAS-STING pathway in cardiac transplantation remains unclear. This study explored the role of cardiomyocytic cGAS in mouse heart transplantation during the ischemia/reperfusion and rejection processes. Methods and Results Cytosolic dsDNA accumulation and cGAS-STING signaling pathway component upregulation were observed in the grafts posttransplantation. The use of cGAS-deficient donor tissues led to significantly prolonged graft survival. The underlying mechanisms involved decreased expression and phosphorylation of downstream proteins, including TANK binding kinase 1 and nuclear factor κB. In parallel, notably diminished expression levels of various proinflammatory cytokines were observed. Accordingly, substantially decreased proportions of macrophages (CD11b+F4/80+) and CD8+ T cells were observed in the spleen. The activation of CD8+ T cells (CD8+CD69+) within the graft and the proportion of effector memory (CD44highCD62Llow) lymphocytes in the spleen were notably decreased. Treatment with the cGAS inhibitor Ru.521 led to significantly prolonged graft survival. Conclusions Cardiomyocytic cGAS plays a critical role by sensing cytosolic dsDNA during cardiac transplantation and could serve as a potential therapeutic target to prevent graft rejection.