Abstract
AimsIn abdominal aortic aneurysm (AAA), macrophages are detected in the proximity of aortic smooth muscle cells (SMCs). We have previously demonstrated in a murine model of AAA that apoptotic SMCs attract monocytes and other leukocytes by producing MCP-1. Here we tested whether infiltrating macrophages also directly contribute to SMC apoptosis.Methods and ResultsUsing a SMC/RAW264.7 macrophage co-culture system, we demonstrated that MCP-1-primed RAWs caused a significantly higher level of apoptosis in SMCs as compared to control macrophages. Next, we detected an enhanced Fas ligand (FasL) mRNA level and membrane FasL protein expression in MCP-1-primed RAWs. Neutralizing FasL blocked SMC apoptosis in the co-culture. In situ proximity ligation assay showed that SMCs exposed to primed macrophages contained higher levels of receptor interacting protein-1 (RIP1)/Caspase 8 containing cell death complexes. Silencing RIP1 conferred apoptosis resistance to SMCs. In the mouse elastase injury model of aneurysm, aneurysm induction increased the level of RIP1/Caspase 8 containing complexes in medial SMCs. Moreover, TUNEL-positive SMCs in aneurysmal tissues were frequently surrounded by CD68+/FasL+ macrophages. Conversely, elastase-treated arteries from MCP-1 knockout mice display a reduction of both macrophage infiltration and FasL expression, which was accompanied by diminished apoptosis of SMCs.ConclusionOur data suggest that MCP-1-primed macrophages are more cytotoxic. MCP-1 appears to modulate macrophage cytotoxicity by increasing the level of membrane bound FasL. Thus, we showed that MCP-1-primed macrophages kill SMCs through a FasL/Fas-Caspase8-RIP1 mediated mechanism.
Highlights
Abdominal aortic aneurysm (AAA) is a common, progressive, and life-threatening degenerative vascular disease
We showed that Monocyte chemoattractant protein-1 (MCP-1)-primed macrophages kill SMCs through a Fas ligand (FasL)/Fas-Caspase8-receptor interacting protein-1 (RIP1) mediated mechanism
MCP-1 Primed-Macrophages Show Higher Cytotoxicity Double immunostaining of murine aneurysmal aortic tissues demonstrated the elevation of SMC apoptosis and accumulation of macrophages in the media of elastase-treated arteries (Fig. 1 A-D)
Summary
Abdominal aortic aneurysm (AAA) is a common, progressive, and life-threatening degenerative vascular disease. AAA is histologically characterized by transmural infiltration of inflammatory cells, depletion of vascular smooth muscle cells (SMCs), and degradation of arterial extracellular matrix (ECM) [1,2]. Depletion of macrophages [5] or preventing them from expressing ECM degrading enzymes such as MMPs [6,7,8] protected mice from developing aneurysm. Elevated MCP-1 mRNA and protein expression has been consistently detected in aneurysmal aortic tissues of human patients as well as animal models [9,10,11,12]. We have previously demonstrated that ectopic administration of recombinant MCP-1 to the arterial wall of PKCd2/2 mice, which has an aneurysm-resistant phenotype, was sufficient to restore local inflammatory response and AAA development [15]. In mixed cultures containing photoreceptors and macrophages, an increasing MCP-1 concentration correlated to an increase in photoreceptor death, though MCP-1 showed no direct effect on photoreceptor survival after depleting macrophages from the cultures [17]
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