High levels of the co-stimulatory immune checkpoint protein GITR drives atherosclerosis through leucocyte recruitment

In this study, we identified Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) – a co-stimulatory immune checkpoint protein – as an important mediator of atherosclerosis-associated inflammation. GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n=100) compared to asymptomatic patients (n=93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12 and C-C-chemokine ligand (CCL) 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. To unravel the mechanisms behind this correlation, we analysed the function of GITR in an atherosclerotic mouse model. Plaque area in Gitr-/-Apoe-/- mice was reduced and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. RNA-sequencing of Gitr-/-Apoe-/- and Apoe-/- monocytes and macrophages revealed altered pathways of cell migration, activation and mitochondrial function. Gitr-/-Apoe-/- monocytes/macrophages displayed decreased integrin levels, reduced recruitment to endothelium and produced less reactive oxygen species. Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.