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

作者：Lee Rueckert Miriam; Silvennoinen Reija; Rotllan Noemi; Judstrom Ilona; Blanco Vaca Francisco; Metso Jari; Jauhiainen Matti; Kovanen Petri T^*; Carles Escola Gil Joan

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(3): 520-527.

DOI：10.1161/ATVBAHA.110.221069

• apolipoprotein A-I
• cholesterol efflux
• macrophages
• mast cell chymase
• reverse cholesterol transport

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 [H-3] cholesterol-labeled J774 macrophages for measurement of the rate of RCT. After 3 hours, H-3-radioactivity was measured in the intestinal lumen contents. Activation of mast cells in the peritoneal cavity depleted human apoA-I pre-beta-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 H-3-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. (Arterioscler Thromb Vasc Biol. 2011;31:520-527.)

• 出版日期2011-3