Suppression of cardiac allograft vasculopathy by a macrophage efferocytosis receptor.

Abstract

Cardiac allograft vasculopathy (CAV) remains a major cause of late morbidity following heart transplantation. Although accumulating evidence implicates innate macrophages in the inflammatory progression of CAV, the underlying mechanisms remain incompletely understood. In murine models of CAV, we identified proteolytic cleavage of proto-oncogene tyrosine-protein kinase MER (MERTK), a key anti-inflammatory receptor on macrophages, as a contributing factor to CAV progression. In a model of CAV, MERTK deficiency accelerated allograft rejection and increased intimal leukocyte infiltration. In contrast, mice expressing a genetically cleavage-resistant MerTK exhibited prolonged graft survival, reduced intimal thickening, diminished immune cell infiltration, and decreased circulating effector T cells. Macrophages isolated from cleavage-resistant MerTK allografts had enhanced mitochondrial metabolism, which correlated with the production of anti-inflammatory cytokines, including IL-10. Mechanistically, coculture experiments demonstrated that activated CD8+ T cells, and not CD4+ or naïve CD8+ T cells, induce MERTK cleavage on macrophages, leading to reduced efferocytosis, increased glycolysis, and increased inflammatory cytokine expression. Together, our findings identify MERTK as a critical regulator of macrophage efferocytosis and metabolism in the context of cardiac transplantation. Our data suggest that MERTK activity protects against CAV progression and that activated T cells may promote allograft injury, in part, by driving MERTK proteolysis.