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

Abstract

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 (Teff) cells into plaque lesion sites, resulting in increased interferon-γ (IFN-γ) expression. Interestingly, Teff-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 Teff cells, VSMCs, and macrophages.

ATVB Distinguished Scientist Award

“…163, 164 Advanced atherosclerotic lesions accumulated more macrophages and T cells when 4-1BB was lacking. 165 Lesions in these mice showed signs of vulnerability, accompanied by reduced SMC survival and collagen production. 165 Interestingly, macrophage glucose metabolism is regulated by the interaction of 4-1BBL with its receptor, leading to increased metabolic activity and cell proliferation.…”

“…165 Lesions in these mice showed signs of vulnerability, accompanied by reduced SMC survival and collagen production. 165 Interestingly, macrophage glucose metabolism is regulated by the interaction of 4-1BBL with its receptor, leading to increased metabolic activity and cell proliferation. 166 Thus, intervention in 4-1BB-4-BBL interactions might display a valuable therapeutic option in macrophage-driven diseases such as atherosclerosis.…”

Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation

“…Circulating CD137L + CD14 + MC was increased in patients with acute ischemic atherosclerotic stroke [74]. CD137 −/− ApoE −/− mice have lower MC and MØ in the aorta [80]. Anti-CD137 monoclonal antibody induced iNOS-positive MØ differentiation in hepatoma tissue in mice [81].…”

The Roles of CD137 Signaling in Atherosclerosis

“…These results indicated that CD137 signaling may contribute to the destabilization of atherosclerotic plaques. Recently, our group determined the CD137-mediated molecular mechanisms whereby activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on T eff cells, VSMCs, and macrophages 87). Briefly, CD137 increases the infiltration of T eff cells into plaque lesion sites, resulting in increased IFN-γ expression.…”