Abstract 203: Silencing of Macrophage Scavenger Receptor SR-A or CD36 Modulates Transcription Factor NF-κB Activity by Distinct Mechanisms

Abstract

Background: Macrophage scavenger receptors SR-A and CD36 play a key role in the pathogenesis of atherosclerosis by participating in the uptake of modified lipoproteins, further leading to formation of foam cells. We have recently shown that RNAi-mediated silencing of these receptors decreases atherogenesis in hyperlipidemic LDLR -/- /ApoB 100/100 mice. Additionally, we discovered that there is a reciprocal regulation mechanism between these two receptors in mouse macrophages. Because there is limited information on the involvement of transcription factor NF-κB to SR-A and CD36 expression, the aim of this study was to investigate the role of NF-κB in the regulation of these receptors in detail. Methods and Results: Lentiviral vector mediated silencing of SR-A and CD36 alters the behavior of transcription factor NF-κB in mouse macrophages. After LPS exposure, SR-A silencing enhanced the classical NF-κB activation measured by activation of NF-κB responsive genes such as M-CSF, MCP-1 and ICAM-1. Moreover, CD36 silencing increased the expression of NF-κB subunit p50 with and without LPS stimulation by 2.7-fold (p<0.001) and 1.4-fold (p<0.01), respectively. Consequently, expressions of several p50 homodimer target genes, such as IL-6 and IL-10, were increased when CD36 was silenced. Finally, two putative NF-κB binding sites and increased p50 binding to SR-A promoter were found by EMSA, suggesting that SR-A is a p50 responsive gene, and that p50 is responsible for the reciprocal upregulation of SR-A when CD36 is silenced. Conclusion: These results suggest that SR-A and CD36 modulate macrophage functions under inflammatory conditions, and imply that SR-A and CD36 are important signal transducers in inflammatory events involving NF-κB.