Tumor necrosis factor superfamily members CD137 and OX40 ligand in vascular inflammation

Abstract

Atherosclerosis, an inflammatory disease, is the major cause of cardiovascular disease - the main cause of death worldwide. T cells are central orchestrators of inflammation in atherosclerosis and critically depend on costimulation for adequate function. Hence, costimulation is pivotal for maintaining immunological homeostasis of inflammatory responses, and a dysregulated immune response may aggravate inflammation in atherosclerosis. Costimulators are therefore of central interest in the pathogenesis of cardiovascular disease. CD137 and OX40 ligand are important costimulatory molecules of the tumor necrosis factor superfamily, but their role in vascular inflammation has been unclear.

We used human biobanks and clinical cohorts in combination with experimental models of atherosclerosis and atherothrombosis to investigate the involvement of CD137 and OX40 ligand in the pathogenesis of cardiovascular disease.

We observed that CD137 was expressed in human and murine atherosclerosis, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. By studying gene expression in cell lines, we found an association between the single nucleotide polymorphism (SNP) rs2453021 and CD137 mRNA expression in human lymphoid cells. The minor allele of this SNP was associated with an increased intima media thickness in human carotid arteries in individuals with risk factors of cardiovascular disease. To study the influence of CD137 activation on atherothrombosis, we turned to an experimental plaque rupture model. We observed that CD137 mRNA expression was higher in ruptured compared to non-ruptured murine carotid lesions. Stimulation of CD137 promoted vascular and systemic inflammation, but did not increase plaque rupture frequency.

Others have reported an association between the SNP rs3850641 in OX40 ligand and cardiovascular risk. We did observe expression of OX40 ligand on endothelial cells within human carotid atherosclerotic lesions, and the OX40 ligand expression was induced by tumor necrosis factor (TNF) in cultured vascular endothelial cells. However, we found no association with the risk for stroke in two independent populations.

In conclusion, the studies in this thesis demonstrate expression of CD137 and OX40 ligand in human atherosclerotic lesions, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. These new insights on the pathophysiology of atherosclerosis warrant further studies of the therapeutic potential of interventions in costimulation for treatment of cardiovascular disease.