The role of tumor necrosis factor-like weak inducer of apoptosis in atherosclerosis via its two different receptors

Abstract

At present, it is commonly accepted that atherosclerosis is a chronic inflammatory disease characterized by disorder of the arterial wall. As one of the inflammatory cytokines of the tumor necrosis factor superfamily, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the formation and progression of atherosclerosis. TWEAK, when binding to its initial receptor, fibroblast growth factor inducible molecule 14 (Fn14), exerts adverse biological functions in atherosclerosis, including dysfunction of endothelial cells, phenotypic change of smooth muscle cells and inflammatory responses of monocytes/macrophages. However, accumulating data supports that, besides Fn14, TWEAK also binds to cluster of differentiation (CD)163, an anti-inflammatory cytokine and a scavenger receptor exclusively expressed by monocytes and macrophages. Furthermore, it has been demonstrated that CD163 is able to internalize TWEAK and likely elicits protective effects in atherosclerosis by terminating inflammation induced by TWEAK. In the present study, the role of TWEAK in atherosclerosis was reviewed, with a predominant focus on CD163 and Fn14 receptors.

Keywords: atherosclerosis; cluster of differentiation 163; fibroblast growth factor inducible molecule 14; receptor; tumor necrosis factor-like weak inducer of apoptosis.

Figure 1.

Fn14 in atherosclerosis. (A) TWEAK/Fn14 axis induces the expression of adhesion molecules, such as E-selectin and ICAM-1, in endothelial cells, which results in the activation and accumulation of local monocytes. TWEAK/Fn14 axis also induces the secretion of MCP-1 and IL-8 in endothelial cells, which may recruit monocytes. (B) TWEAK/Fn14 axis elicits the function of promoting proliferation and migration of VSMCs. Expression of the thrombosis mediators, TF and PAI-1, may be induced by this axis. (C) TWEAK/Fn14 axis may induce the expression of MCP-1 and IL-8 in activated monocytes and MMP-9 and HMGB1 in macrophages. The TWEAK/Fn14 axis also assists NADPH oxidase activation, thereby generating oxygen species in macrophages. In addition, the axis alters macrophage trafficking and increases lipid uptake of macrophages. TWEAK, tumor necrosis factor-like weak inducer of apoptosis; Fn14, fibroblast growth factor inducible molecule 14; ICAM, intercellular adhesion molecule; MCP-1, monocyte chemoattractant protein-1; IL, interleukin; VSMCs, vascular smooth muscle cells; MMP, matrix metalloproteinases; HMGB1, high mobility group box 1; Ox-LDL, oxidized low density lipoprotein; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor.

Figure 2.

CD163 in atherosclerosis. (A) Hb may be scavenged by CD163. Once released from erythrocytes, Hb binds to Hp to form complexes, resulting in exposure of a neo-epitope that is able to combine with CD163. Once this receptor-ligand complex is delivered to early endosomes through endocytosis, CD163 enters an alternative pathway by dissociating and is recycled to cell membrane, whereas Hb-Hp continues its metabolism within the lysosomes. Regulated by the rate-limiting enzyme, HO-1, Hb-Hp metabolism produces anti-inflammatory molecules, including biliverdin, Fe²⁺ and CO. Conversely, HO-1 and CD163 production may be upregulated by IL-10, whose production is triggered by Hb-Hp-CD163 binding through activating the intracellular signaling pathway. (B) CD163-expressing macrophages recognize and internalize TWEAK, resulting in a decrease of sTWEAK. TWEAK, tumor necrosis factor-like weak inducer of apoptosis; sTWEAK, soluble TWEAK; HO-1, heme oxygenase-1; CD163, cluster of differentiation 163; Hb, hemoglobin; Hp, haptoglobin; IL, interleukin; CO, carbon monoxide; Fe²⁺, Iron²⁺.