Atheroesclerosis

Vascular Medicine
CD137 (4 –1BB) Deficiency Reduces Atherosclerosis in Hyperlipidemic Mice
Hyung Jun Jeon, PhD*; Jae-Hoon Choi, DVM, PhD*; In-Hyuk Jung, MSc*; Jong-Gil Park, MSc; Mi-Ran Lee, MSc; Mi-Ni Lee, MSc; Bora Kim, MSc; Ji-Young Yoo, BSc; Se-Jin Jeong, BSc; Dae-Yong Kim, DVM, PhD; Jeong Euy Park, MD, PhD; Hyun-Young Park, MD, PhD; KyuBum Kwack, PhD; Beom Kyu Choi, PhD; Byoung S. Kwon,PhD; Goo Taeg Oh, DVM, PhD
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 atherosclerosisand 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, whichwas attributed to the downregulation of cytokines such as interferon- , monocyte chemoattractant protein-1, and tumor necrosis factor- . 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 signalingactivated 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. (Circulation. 2010;121:1124-1133.) Key Words: atherosclerosis CD137 CD137 ligand immune systemtherosclerosis is an inflammatory disease of the arterial wall that involves both innate and adaptive T-cell– driven immunoinflammatory responses.1–3 Accumulating evidence on human disease suggests that autoantigens are involved in the promotion of atherosclerosis. In T cells isolated from fresh human plaques, oxidized LDL (oxLDL) is a major autoantigen that triggers an immune response thatinvolves activation of T cells and subsequent stimulation of local cytokine release by monocytes/macrophages, such as monocyte chemoattractant protein-1 (MCP-1).4 –7 T-cell activation is further enhanced by ligand binding to the costimulatory receptors CD40, CD137, and OX40, which are expressed on the cell surface. Enhanced T-cell activation by ligand binding to costimulatory receptors significantlyaugments cytokine release by monocytes/macrophages, further exacerbating inflammation and promoting atherosclerosis.8 –11

A

Here, we demonstrate that CD137 contributes to T-cell activation and generation of interferon (IFN)- in atherosclerotic mice. IFN- , in turn, induces monocytes/macrophages to augment proinflammatory cytokine production through a positive feedback mechanism, therebyfacilitating atherogenic plaque formation.

Clinical Perspective on p 1133
Several recent reports suggest that CD137 and its ligand, CD137L, are important contributory factors to colitis, osteoclastogenesis, and toll-like receptor signaling in macrophages.12–14 CD137L is a type II membrane glycoprotein of the tumor necrosis factor (TNF) receptor superfamily expressed on monocytes, macrophages,dendritic cells, and activated B cells. In general, TNF receptor superfamily members are initiators of inflammatory disease. The receptor

Received May 26, 2009; accepted January 11, 2010. From the Division of Life and Pharmaceutical Science (H.J.J., J.-H.C., I.-H.J., J.-G.P., M.-R.L., M.-N.L., B.K., J.-Y.Y., S.-J.J., G.T.O.), Ewha Womans University, Seoul, Korea; Laboratory of Cellular Physiology...