Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage
Abca1/g1
deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis.
We hypothesized that macrophage
Abca1/g1
deficiency activates the inflammasome. In
Ldlr
-/-
mice fed a Western type diet (WTD), macrophage
Abca1/g1
deficiency increased IL-1β and IL-18 plasma levels (2-fold;
P
<0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components
Nlrp3
or
caspase-1
in macrophage
Abca1/g1
knockouts reversed the increase in plasma IL-18 levels (
P
<0.001), indicating these changes were inflammasome dependent. We found that macrophage
Abca1/g1
deficiency induced caspase-1 cleavage in splenic CD115
+
monocytes and CD11b
+
macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage
Abca1/g1
deficiency led to an increased splenic population of monocytes (2.5-fold;
P
<0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold;
P
<0.01), likely contributing to inflammasome activation.
Caspase-1
deficiency decreased atherosclerosis in macrophage
Abca1/g1
deficient
Ldlr
-/-
mice fed WTD for 8 weeks (225822 vs 138606 μm
2
;
P
<0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage
Abca1/g1
knockouts decreased plasma IL-18 levels (
P
<0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold;
P
<0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.