title: Monocyte chemoattractant protein-1 (MCP-1) regulates macrophage cytotoxicity in abdominal aortic aneurysm.
abstract: OBJECTIVE
  In 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.
  
  
  RESULTS
  Using 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, United States of America.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Morgan
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, United States of America.
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Luye Pharma Group, Yantai, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Dou
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison, Wisconsin, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D018920:Coculture Techniques; D053222:Fas Ligand Protein / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000473:pathology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053222:Fas Ligand Protein; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D053148:Caspase 3; D053181:Caspase 8