Activation of Nlrp3 inflammasomes enhances macrophage lipid-deposition and migration: implication of a novel role of inflammasome in atherogenesis.
Although Nlrp3 inflammasome activation in macrophages has been shown to be critical for the development of atherosclerosis upon atherogenic stimuli, it remains unknown whether activated Nlrp3 inflammasomes by other non-atherogenic stimuli induce alterations in macrophages that may contribute in the concert with other factors to atherogenesis. Thus, the present study tested the hypothesis that activation of Nlrp3 inflammasomes by ATP, which is a classical non-lipid danger stimulus, enhances the migration of macrophage and increases lipids deposition in macrophages accelerating foam cell formation. We first demonstrated that extracellular ATP (2.5 mM) markedly increased the formation and activation of Nlrp3 inflammasomes in bone marrow macrophages (BMMs) from wild type (Asc⁺/⁺) mice resulting in activation of caspase-1 and IL-1β production. In these Asc⁺/⁺ macrophages, such stimulation of inflammasomes by non-lipid ATP was similar to those induced by atherogenic stimuli such as cholesterol crystals or 7-ketocholesterol. Both non-lipid and lipid forms of stimuli induced formation and activation of Nlrp3 inflammasomes, which were prevented by Asc gene deletion. Interestingly, Asc⁺/⁺ BMMs had dramatic lipids accumulation after stimulation with ATP. Further, we demonstrated that large amount of cholesterol was accumulated in lysosomes of Asc⁺/⁺ BMMs when inflammasomes were activated by ATP. Such intracellular and lysosomal lipids deposition was not observed in Asc⁻/⁻ BMMs and also prevented by caspase-1 inhibitor WEHD. In addition, in vitro and in vivo experiments revealed that migration of Asc⁺/⁺ BMMs increased due to stimulation of Nlrp3 inflammasomes, which was markedly attenuated in Asc⁻/⁻ BMMs. Together, these results suggest that activation of Nlrp3 inflammasomes remarkably increases the susceptibility of macrophages to lipid deposition and their migration ability. Such novel action of inflammasomes may facilitate entry or retention of macrophages into the arterial wall, where they form foam cells and ultimately induce atherosclerosis.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Xiang
X
Li
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Yang
Y
Zhang
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Min
M
Xia
Department of Molecular Biology, Medical School Essen, University of Duisburg-Essen, Essen, Germany.
Erich
E
Gulbins
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Krishna M
KM
Boini
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Pin-Lan
PL
Li
D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D050197:Atherosclerosis / Q000378:metabolism*; D001391:Azo Compounds; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009842:Oligopeptides; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051017:Apoptosis Regulatory Proteins; D001391:Azo Compounds; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009842:Oligopeptides; C498534:Pycard protein, mouse; C513343:tryptophyl-glutamyl-histidyl-aspartic acid; C011049:oil red O