Abstract
BackgroundSignal regulate protein α (SIRPα) is involved in many functional aspects of monocytes. Here we investigate the role of SIRPα in regulating β2 integrin-mediated monocyte adhesion, transendothelial migration (TEM) and phagocytosis.Methodology/Principal FindingsTHP-1 monocytes/macropahges treated with advanced glycation end products (AGEs) resulted in a decrease of SIRPα expression but an increase of β2 integrin cell surface expression and β2 integrin-mediated adhesion to tumor necrosis factor-α (TNFα)–stimulated human microvascular endothelial cell (HMEC-1) monolayers. In contrast, SIRPα overexpression in THP-1 cells showed a significant less monocyte chemotactic protein-1 (MCP-1)–triggered cell surface expression of β2 integrins, in particular CD11b/CD18. SIRPα overexpression reduced β2 integrin-mediated firm adhesion of THP-1 cells to either TNFα–stimulated HMEC-1 monolayers or to immobilized intercellular adhesion molecule-1 (ICAM-1). SIRPα overexpression also reduced MCP-1–initiated migration of THP-1 cells across TNFα–stimulated HMEC-1 monolayers. Furthermore, β2 integrin-mediated THP-1 cell spreading and actin polymerization in response to MCP-1, and phagocytosis of bacteria were both inhibited by SIRPα overexpression.Conclusions/SignificanceSIRPα negatively regulates β2 integrin-mediated monocyte adhesion, transendothelial migration and phagocytosis, thus may serve as a critical molecule in preventing excessive activation and accumulation of monocytes in the arterial wall during early stage of atherosclerosis.
Highlights
Recruitment of monocytes from circulation to inflamed tissues plays a pivotal role in the initiation and progression of atherosclerosis [1,2,3]
The downregulation of Signal regulate protein a (SIRPa) in AGEs–treated THP-1 cells is contrast to that of receptor for advanced glycation end products (RAGE) and junctional adhesion molecule-like protein (JAML), which expression levels are both increased after AGEs treatment (Zen et al, unpublished)
By studying the leukocyte b2 integrin-mediated functional changes in THP-1 cells after downregulation or overexpression of SIRPa level, we show that SIRPa negatively regulates b2 integrin-mediated THP-1 cell inflammatory responses, such as adhesion, transendothelial migration and phagocytosis
Summary
Recruitment of monocytes from circulation to inflamed tissues plays a pivotal role in the initiation and progression of atherosclerosis [1,2,3]. E- and Pselectins are involved in the initial reversible adherence of monocytes to the endothelial cell monolayers [5]. The following firm adhesion is mediated by monocyte b2 integrins,including CD11a/CD18 and CD11b/CD18,that recognize vascular cell adhesion molecule-1(VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells [6]. Firm adhesion of monocytes requires activation of integrins, which can be triggered by agonist-induced activation of G protein–coupled chemokine receptors [7]. Monocytes express CC chemokine receptor 2 (CCR2), which binds monocyte chemoattractant protein-1 (MCP1), leading to b2 integrin-mediated firm adhesion and subsequent transmigration of adhered monocytes through the vascular endothelium [8]. Signal regulate protein a (SIRPa) is involved in many functional aspects of monocytes. We investigate the role of SIRPa in regulating b2 integrin-mediated monocyte adhesion, transendothelial migration (TEM) and phagocytosis
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