Increased Carotid Artery Lesion Inflammation Upon Treatment With the CD137 Agonistic Antibody 2A

Abstract

Background: Increased inflammatory activity destabilizes the atherosclerotic lesion and may lead to atherothrombosis and symptomatic cardiovascular disease. Co-stimulatory molecules, such as CD137, are key regulators of inflammation, and CD137 activity regulates inflammation in experimental atherosclerosis. Here, we hypothesized that CD137 activation promotes carotid artery inflammation and atherothrombosis. Methods and Results:In a model of inducible atherothrombosis with surgical ligation of the right carotid artery and a subsequent placement of a polyethene cuff, elevated levels of CD137 and CD137 ligand mRNA in atherothrombotic vs. non-atherothrombotic murine carotid lesions was observed. Mice treated with the CD137 agonistic antibody 2A showed signs of increased inflammation in the aorta and a higher proportion of CD8 + T cells in spleen and blood. In carotid lesions of 2A-treated mice, significantly higher counts of CD8 + and major histocompatibility (MHC)-class II molecule I-A b+ cells were observed. Treatment with the CD137 agonistic antibody 2A did not significantly affect the atherothrombosis frequency in 16-week-old mice in this model. Conclusions:Levels of CD137 and CD137 ligand mRNA were higher in advanced atherosclerotic disease compared to control vessels, and treatment with the CD137 agonistic antibody 2A, in a murine model for inducible atherothrombosis promoted vascular inflammation, but had no significant effect on atherothrombosis frequency at this early disease stage.

Hypermethylation of the Micro-RNA 145 Promoter Is the Key Regulator for NLRP3 Inflammasome-Induced Activation and Plaque Formation

“…Because NLRP3 and IL-1β were not the direct targets of miR-145, as evidenced by the bioinformatics analysis, we hypothesized that miR-145 represses NLRP3 activity through targeting another inflammation pathway. Recent studies have demonstrated that CD137/NFATc1 is an important signaling pathway in VSMC inflammation and plaque formation 18 , 41 , 42 . We previously observed elevated IL-1β levels in VSMC supernatants when CD137 was activated (data not shown).…”

Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

“…Additionally, soluble CD137, which is released by leukocytes after activation and is elevated in autoimmunity (42,57), correlates with increased risk of cardiovascular events in patients with acute coronary syndrome (73, 74). In hyperlipidemic mouse models, global CD137 deficiency decreases plaque lesion size and diminishes monocyte/macrophage infiltration (27), whereas agonistic CD137 activation facilitates plaque development (38,60). Bone marrow transplant experiments have hinted at a proatherogenic role for CD137 in circulating blood cells (27), but the specific circulating populations responsible have not yet been defined.…”

Contributions of Costimulatory Molecule CD137 in Endothelial Cells

“…The authors also reported increased expression of CD137 mRNA in murine carotid atherosclerotic and atherothrombotic lesions compared with control vessels. 32 Zhang et al showed that 3 single nucleotide polymorphisms (rs161827, rs161818, and rs161810) in the CD137 gene were associated with ischemic stroke in patients with carotid lesions; moreover, rs161827 is significantly associated with stroke in patients with diabetes mellitus. 33 These results suggest that functional single nucleotide polymorphisms of CD137 may affect the development of noncardiac vascular atherosclerosis by changing the expression and activity of CD137, thereby modulating the downstream biological effects.…”