title: Induction of CCR2-dependent macrophage accumulation by oxidized phospholipids in the air-pouch model of inflammation.
abstract: OBJECTIVE
  Macrophages are key players in the pathogenesis of rheumatoid synovitis as well as in atherosclerosis. To determine whether atherogenic oxidized phospholipids potentially contribute to synovial inflammation and subsequent monocyte/macrophage recruitment, we examined the effects of oxidized 1- palmitoyl-2-arachidonoyl-sn-3-glycero-phosphorylcholine (OxPAPC) on chemokine expression and leukocyte recruitment in a facsimile synovium in vivo using the murine air-pouch model.
  
  
  METHODS
  Air pouches were raised by 2 injections of sterile air, and inflammation was induced by injecting either lipopolysaccharide (LPS) or OxPAPC into the pouch lumen. Inflammation was assessed by analysis of inflammatory gene expression using reverse transcription-polymerase chain reaction or immunohistochemical analysis, and leukocytes were quantified in the lavage fluid and in the pouch wall after staining with Giemsa or after enzymatic digestion followed by fluorescence-activated cell sorter analysis.
  
  
  RESULTS
  Application of OxPAPC resulted in selective recruitment of monocyte/macrophages into the air-pouch wall, but not in the lumen. In contrast, LPS induced both monocyte and neutrophil accumulation in the pouch lumen as well as in the wall. LPS, but not OxPAPC, induced the expression of adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. OxPAPC increased the expression of the CCR2 ligands monocyte chemotactic protein 1 (MCP-1), MCP-3, and MCP-5, as well as RANTES and growth-related oncogene alpha (GROalpha), while it down-regulated the expression of CCR2 on macrophages. Moreover, oxidized phospholipid-induced macrophage accumulation was abrogated in CCR2-/- mice.
  
  
  CONCLUSIONS
  These data demonstrate that oxidized phospholipids trigger a type of inflammatory response that leads to selective macrophage accumulation in vivo, a process relevant for the pathogenesis of chronic inflammatory rheumatic diseases.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Elena
authors.initials: E
authors.lastname: Galkina
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
mesh_terms: D000818:Animals; D043422:Carboxypeptidases A / Q000032:analysis; D018932:Chemokine CCL2 / Q000032:analysis; D018946:Chemokine CCL5 / Q000032:analysis; D054360:Chemokine CXCL1 / Q000032:analysis; D019040:E-Selectin / Q000032:analysis; D005260:Female; D006652:Histological Techniques; D007249:Inflammation / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000032:analysis; D009000:Monocytes / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D019007:P-Selectin / Q000032:analysis; D010713:Phosphatidylcholines / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000502:physiology*; D012216:Rheumatic Diseases / Q000503:physiopathology; D013583:Synovial Membrane / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: C515334:CCR2 protein, human; C491224:Ccl12 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D019040:E-Selectin; D008070:Lipopolysaccharides; D018945:Monocyte Chemoattractant Proteins; D019007:P-Selectin; D010713:Phosphatidylcholines; D054390:Receptors, CCR2; D019010:Vascular Cell Adhesion Molecule-1; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D018799:Intercellular Adhesion Molecule-1; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse