title: Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse.
abstract: OBJECTIVE
  Chymase released by activated mast cells degrades high-density lipoproteins. We evaluated whether local activation of mast cells would attenuate cholesterol efflux from neighboring macrophage foam cells, thereby disrupting the entire in vivo pathway of macrophage-specific reverse cholesterol transport (RCT).
  
  
  RESULTS
  C57Bl/6J mice received intraperitoneal injections of the mast cell-degranulating compound 48/80 to induce peritoneal mast cell activation, human apolipoprotein A-I (apoA-I) to stimulate RCT, and [(3)H]cholesterol-labeled J774 macrophages for measurement of the rate of RCT. After 3 hours, (3)H-radioactivity was measured in the intestinal lumen contents. Activation of mast cells in the peritoneal cavity depleted human apoA-I pre-β-migrating species, impairing the ability of the peritoneal fluid to efficiently promote cholesterol efflux from cultured macrophages. Moreover, intact but not chymase-treated (proteolyzed) apoA-I accelerated the transfer of macrophage-derived (3)H- radioactivity to the intestinal contents. Importantly, stimulation of RCT by human apoA-I was fully blocked by 48/80 in mast cell-competent wild-type C57Bl/6J mice but not in mast cell-deficient W-sash c-kit mutant mice. The ability of intraperitoneally administered phospholipid vesicles to promote RCT in wild-type mice was not blocked by 48/80, supporting the notion that mast cell-dependent proteolysis of the intraperitoneally administered apoA-I was responsible for RCT inhibition.
  
  
  CONCLUSIONS
  Overall, our results suggest that tissue-specific activation of mast cells with ensuing release of chymase is able to proteolytically inactivate apoA-I in the microenvironment of the activated mast cells, thus locally impairing the initiation of macrophage RCT in vivo.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee-Rueckert
authors.forename: Reija
authors.initials: R
authors.lastname: Silvennoinen
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.forename: Ilona
authors.initials: I
authors.lastname: Judström
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco-Vaca
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Escola-Gil
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000378:metabolism; D001692:Biological Transport; D002450:Cell Communication / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D053818:Chymases / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000378:metabolism* / Q000637:transplantation; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010743:Phospholipids / Q000008:administration & dosage; D011489:Protein Denaturation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D013997:Time Factors; D014316:Tritium; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D010743:Phospholipids; D014316:Tritium; D003189:p-Methoxy-N-methylphenethylamine; D002784:Cholesterol; D019009:Proto-Oncogene Proteins c-kit; D053818:Chymases