CD137 Is Expressed in Human Atherosclerosis and Promotes Development of Plaque Inflammation in Hypercholesterolemic Mice

Abstract

Background— Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis. Methods and Results— This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E–deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8 + cells, and expression of the murine major histocompatibility complex class II molecule I-A b increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines. Conclusions— Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…For instance, an agonistic anti-CD137 mitigated disease in murine autoimmune models, 99,100 but exacerbated atherosclerosis in Apoe -/-mice. 101 A lethal systemic proinflammatory cytokine storm was unfortunately induced in healthy volunteers by targeting CD28 with agonistic anti-CD28. 102 Therefore, the use of some therapeutics that are directed toward certain costimulatory molecules may be a powerful but dangerous approach to treating CVD.…”

Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis – A review of the experimental evidence

“…In contrast to CD4 + T helper cells, CD8 + cytolytic T lymphocytes have not been extensively studied, even though CD8 + T cells are abundant in atherosclerotic plaques and they have been shown to be activated in hypercholesterolemic Apoe -/-mice (33). Activation of CD8 + T cells has also been associated with increased plaque formation in these mice (34). In apparent contrast with these observations, atherosclerosis protection achieved by immunization with apolipoprotein B (apoB) peptide has been suggested to involve CD8 + T cells (35).…”

Reverse Signaling through the Co-Stimulatory Ligand, CD137L, as a Critical Mediator of Sterile Inflammation

“…In renal ischemia-reperfusion injury, CD137L signals are required to recruit neutrophils (Kim et al, 2012a). The endothelial cells of vessels in atherosclerotic lesions express both CD137 and CD137L (Jeon et al, 2010;Olofsson et al, 2008). Since CD137 and CD137L signals can promote leukocyte transmigration by inducing pro-inflammatory cytokines and chemokines and by upregulating cell adhesion molecules in endothelial cells (Jeon et al, 2010), endothelial cells seem to activate either CD137-or CD137L-expressing leukocytes during transmigration into inflammation sites.…”