ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis.
BACKGROUND
Antiatherogenic effects of plasma high-density lipoprotein (HDL) include the ability to inhibit apoptosis of macrophage foam cells. The ATP-binding cassette transporters ABCA1 and ABCG1 have a major role in promoting cholesterol efflux from macrophages to apolipoprotein A-1 and HDL and are upregulated during the phagocytosis of apoptotic cells (efferocytosis).


OBJECTIVE
The goal of this study was to determine the roles of ABCA1 and ABCG1 in preserving the viability of macrophages during efferocytosis.


RESULTS
We show that despite similar clearance of apoptotic cells, peritoneal macrophages from Abca1(-/-)Abcg1(-/-), Abcg1(-/-), and, to a lesser extent, Abca1(-/-) mice are much more prone to apoptosis during efferocytosis compared to wild-type cells. Similar findings were observed following incubations with oxidized phospholipids, and the ability of HDL to protect against oxidized phospholipid-induced apoptosis was markedly reduced in Abca1(-/-)Abcg1(-/-) and Abcg1(-/-) cells. These effects were independent of any role of ABCA1 and ABCG1 in mediating oxidized phospholipid efflux but were reversed by cyclodextrin-mediated cholesterol efflux. The apoptotic response observed in Abca1(-/-)Abcg1(-/-) macrophages after oxidized phospholipid exposure or engulfment of apoptotic cells was dependent on an excessive oxidative burst secondary to enhanced assembly of NADPH oxidase (NOX)2 complexes, leading to sustained Jnk activation which turned on the apoptotic cell death program. Increased NOX2 assembly required Toll-like receptors 2/4 and MyD88 signaling, which are known to be enhanced in transporter deficient cells in a lipid raft-dependent fashion.


CONCLUSIONS
We identified a new beneficial role of ABCA1, ABCG1 and HDL in dampening the oxidative burst and preserving viability of macrophages following exposure to oxidized phospholipids and/or apoptotic cells.
Yvan-Charvet
Laurent
L
Division of Molecular Medicine, Department of Medicine, 630 W 168th St, Columbia University, New York, NY 10032, USA. ly2159@columbia.edu
Pagler
Tamara A
TA
Seimon
Tracie A
TA
Thorp
Edward
E
Welch
Carrie L
CL
Witztum
Joseph L
JL
Tabas
Ira
I
Tall
Alan R
AR
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D008074:Lipoproteins / Q000235:genetics / Q000502:physiology*; D008075:Lipoproteins, HDL / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D048670:MAP Kinase Kinase 4