CD137 (4–1BB) Deficiency Reduces Atherosclerosis in Hyperlipidemic Mice

Abstract

Background— The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. Methods and Results— We generated CD137-deficient apolipoprotein E–knockout mice ( ApoE −/− CD137 −/− ) and LDL-receptor–knockout mice ( Ldlr −/− CD137 −/− ) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-γ, monocyte chemoattractant protein-1, and tumor necrosis factor-α. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. Conclusions— CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.

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

“…As described below, CD137L signaling in non-hematopoietic cells is essential for tissue inflammation (Jeon et al, 2010;Kim et al, 2012a). Epithelial cells are the cells most commonly damaged by intracellular and extracellular insults, and therefore often initiate inflammation (Swamy et al, 2010).…”

“…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.…”

Increased Soluble CD137 Levels and CD4+ T‐Cell‐Associated Expression of CD137 in Acute Atherothrombotic Stroke

“…CD137 is expressed by various immune cells, such as activated CD4+ and CD8+ T lymphocytes, natural killer (NK) cells, CD4+CD25+ regulatory T cells (Treg), monocytes, neutrophils, mast cells, eosinophils, and dendritic cells9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 as well as nonimmune cells such as endothelial cells and vascular smooth muscle cells 10. The ligand of CD137 (CD137L) is primarily expressed on antigen‐presenting cells (dendritic cells, monocytes/macrophages, and B cells), human primary T cells22 and cardiac myocytes in myocarditis and aortic tissue in arteritis 23, 24.…”

“…Our study demonstrated that plasma sCD137 levels tended to decrease following treatment, in parallel with the decreasing serum MMP‐9 levels after statin therapy 42, 43. Unlike membrane‐bound CD137 that delivers a potent stimulatory signal to activate T cells, sCD137 may enhance immune responses by reverse signaling, as shown in an ex vivo study by Jeon et al ., who showed that sCD137‐treated macrophages expressing CD137L can produce MCP‐1 and TNF‐α 11. Taking our additional results into consideration, i.e., the positive correlation of sCD137 levels with brain infarct volume and disease severity, the shedding of CD137 from lymphocytes, such as activated CD4+ T cells, may function as a positive feedback mechanism to further promote brain ischemia‐related inflammation that has been triggered by the local cell–cell CD137/CD137L interaction in the acute stage of stroke.…”

“…In addition, increased expression of another TNFSF member, CD137 (4‐1BB, TNFRSF9), has been reported on T cells in human atherosclerotic plaques and the endothelium, and it is able to induce adhesion molecule expression in the endothelium and reduce smooth muscle cell proliferation upon activation by CD137 ligands (CD137L, 4‐1BBL, TNFSF9) 10. In an experimental study of CD137‐deficient apolipoprotein E‐knockout mice ( ApoE − / − CD137 − / − ) and low‐density lipoprotein (LDL)‐receptor–knockout mice ( Ldlr − / − CD137 − / − ), the lack of CD137 produced fewer atherosclerotic plaques in these two models, whereas stimulation of CD137L signaling by soluble CD137 activated monocytes/macrophages and augmented the secretion of proinflammatory cytokines in atherosclerotic plagues 11, 12. Furthermore, two distinct studies reported that patients with acute coronary syndromes demonstrated significantly higher CD137 expression in monocytes and greater levels of serum soluble CD137 (sCD137) than control groups 13, 14.…”