Abstract
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.
Highlights
The inflammasome is intracellular inflammatory machinery that has been reported to switch on the inflammatory response of tissues or organs to various danger signals [1,2]
The present study demonstrated that formation and activation of Nod-like receptor family pyrin domain containing 3 (Nlrp3) inflammasomes induced by the non-atherogenic danger signal ATP was associated with increased lipid deposition in lysosomes and enhanced migration ability in macrophages
apoptosisassociated speck-like protein (Asc) gene deletion markedly abolished Nlrp3 inflammasome activation, attenuated lysosomal lipid deposition and decreased macrophage migration ability. These results suggest that the formation and activation of Nlrp3 inflammasomes by nonatherogenic stimulation alters macrophage function and increase the susceptibility of these cells to formation of foam cells
Summary
The inflammasome is intracellular inflammatory machinery that has been reported to switch on the inflammatory response of tissues or organs to various danger signals [1,2]. There is substantial evidence showing that accumulated lipids in macrophages exist in cytoplasmic inclusions as cholesteryl ester inclusions and in lipid-swollen lysosomes as both free cholesterol and cholesteryl ester during atherosclerosis [14,15] This lipid deposition in the cytosol and lysosomes critically contributes to the foam cell formation in arterial walls, resulting in arterial wall fibrosis or atherosclerosis [16]. It is imperative to know whether non-lipid danger signals activating the inflammasome in macrophages may alter lipid metabolism or transport in these cells and thereby increase the potential to lead to the formation of foam cells and sclerosis in arterial walls This is particular relevant to the development of atherosclerosis in patients with chronic inflammation or with chronic or remittent bacterial or viral infections, where they may have activated inflammasomes through damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs)
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