CD137‐inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice

CD137 (4‐1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in atherosclerotic plaques, and to promote lesion formation. However, the role of CD137 in mediating atherosclerotic plaque stability and the possible underlying molecular and cellular mechanisms are poorly understood. Here, apolipoprotein E‐deficient ( ApoE ‐/‐ ) and CD137‐deficient ApoE ‐/‐ ( ApoE ‐/‐ CD137 ‐/‐ ) mice fed a chow diet for 66 wk were used. CD137 induces plaque instability, which is characterized by increased plaque necrosis, decreased collagen content, decreased vascular smooth muscle cell (VSMC) content, and increased macrophage infiltration. CD137 also increases the infiltration of effector T (T eff ) cells into plaque lesion sites, resulting in increased interferon‐γ (IFN‐γ) expression. Interestingly, T eff ‐cell‐derived IFN‐γ inhibits collagen synthesis in atherosclerotic plaques. Furthermore, CD137 activation increases the apoptosis of VSMCs, possibly by decreasing the antiapoptotic regulator, Bcl‐2, and subsequently up‐regulating cleaved caspase‐3. In macrophages, activation of CD137 signaling boosted the oxidized low density lipoprotein‐induced expression of matrix metalloproteinase 9 via the p38 mitogen‐activated protein kinase and extracellular signal‐regulated kinase1/2 signaling pathways. In summary, activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on T eff cells, VSMCs, and macrophages.—Jung, I.‐H., Choi, J.‐H., Jin, J., Jeong, S.‐J., Jeon, S., Lim, C., Lee, M.‐R., Yoo, J.‐Y., Sonn, S.‐K., Kim, Y. H., Choi, B. K., Kwon, B. S., Seoh, J.‐Y., Lee, C. W., Kim, D.‐Y., Oh, G. T. CD137‐inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice. FASEB J. 28, 4779–4791 (2014). www.fasebj.org