Mast Cell Activation In Vivo Impairs the Macrophage Reverse Cholesterol Transport Pathway in the Mouse

Miriam Lee-Rueckert, Reija Silvennoinen, Noemi Rotllan, Ilona Judstrom, Francisco Blanco-Vaca, Jari Metso, Matti Jauhiainen, Petri T. Kovanen, Joan Carles Escola-Gil

Research output: Contribution to journalArticleScientificpeer-review

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).
Methods and 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 [3H]cholesterol-labeled J774 macrophages for measurement of the rate of RCT. After 3 hours, 3H-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 3H- 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.
Conclusion—
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.
Original languageEnglish
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number3
Pages (from-to)520-527
Number of pages8
ISSN1079-5642
DOIs
Publication statusPublished - Mar 2011
MoE publication typeA1 Journal article-refereed

Fields of Science

  • apolipoprotein A-I
  • cholesterol efflux
  • macrophages
  • mast cell chymase
  • reverse cholesterol transport
  • APOLIPOPROTEIN-A-I
  • HIGH-DENSITY-LIPOPROTEINS
  • PRE-BETA-HDL
  • PHOSPHOLIPID TRANSFER PROTEIN
  • TRANSGENIC MICE
  • APOA-I
  • INFLAMMATORY DISEASE
  • LIPID EFFLUX
  • HUMAN PLASMA
  • PARTICLES
  • 3111 Biomedicine

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