TRAIL/DR5 Signaling Promotes Macrophage Foam Cell Formation by Modulating Scavenger Receptor Expression

Fang Fang Liu,Yan Wang,Fan Jiang,Yun Zhang,Xiao Wu,Shawn B Bratton

doi:10.1371/journal.pone.0087059

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to have protective effects against atherosclerosis. However, whether TRAIL has any effects on expression of macrophage scavenger receptors and lipid uptake has not yet been studied. Macrophage lines RAW264.7 and THP-1, and mouse primary peritoneal macrophages, were cultured in vitro and treated with recombinant human TRAIL. Real-time PCR and western blot were performed to measure mRNA and protein expressions. Foam cell formation was assessed by internalization of acetylated and oxidized low-density lipoproteins (LDL). Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. We found that TRAIL treatment increased expression of scavenger receptor (SR)-AI and SR-BI in a time- and dose-dependent manner, and this effect was accompanied by increased foam cell formation. These effects of TRAIL were abolished by a TRAIL neutralizing antibody or in DR5 receptor-deficient macrophages. The increased LDL uptake by TRAIL was blocked by SR-AI gene silencing or the SR-AI inhibitor poly(I:C), while SR-BI blockade with BLT-1 had no effect. TRAIL-induced SR-AI expression was blocked by the inhibitor of p38 mitogen-activated protein kinase, but not by inhibitors of ERK1/2 or JNK. TRAIL also induced apoptosis in macrophages. In contrast to macrophages, TRAIL showed little effects on SR expression or apoptosis in vascular smooth muscle cells. In conclusion, our results demonstrate that TRAIL promotes macrophage lipid uptake via SR-AI upregulation through activation of the p38 pathway.

Highlights

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), known as Apo-2 ligand (Apo-2L) or TNFSF10, is a member of the TNF super family of cytokines [1,2,3]
To further confirm that the effects of TRAIL on macrophage lipid uptake were relevant to foam cell formation, we pretreated RAW264.7 and THP-1 cells with TRAIL and loaded the cells with oxLDL for a longer period of 48 hr
These results demonstrated that TRAIL induced robust stimulatory effects on lipid uptake and foam cell formation in cultured macrophages

Summary

Introduction

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), known as Apo-2 ligand (Apo-2L) or TNFSF10, is a member of the TNF super family of cytokines [1,2,3]. TRAIL ligation to DR4/5 receptors causes recruitment of the adaptor molecule FADD and apoptosis initiators caspase-8 and 210, forming a primary signaling complex called death-inducing signaling complex (DISC) [1,2,4]. TRAIL may trigger formation of a secondary signaling complex containing FADD, caspase-8, RIP1, TRAF2, TRADD and NEMO, in which the ligand and cognate receptor are absent. This signaling route activates nuclear factor (NF)-kB and mitogen-activated protein kinases (MAPKs) such as JNK and p38, and is thought to have a pro-survival role [1,2,4]

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Results

Conclusion