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Reversal of ATP‐Induced NLRP3 Inflammasome Activation and Lipids Deposition in Macrophages from Mice Lacking Apoptosis‐associated Speck‐like Protein (ASC) Gene
Author(s) -
Li Xiang,
Zhang Yang,
Xia Min,
Boini Krishna M.,
Li PinLan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.686.11
Subject(s) - inflammasome , chemistry , microbiology and biotechnology , colocalization , extracellular , oil red o , foam cell , intracellular , biochemistry , cholesterol , lipoprotein , biology , gene , receptor , adipogenesis
Although NLRP3 inflammasome activation in macrophages (Mφ) 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 are also involved in atherogenesis. The present study tested a hypothesis that activation of NLRP3 inflammasomes by ATP, which is generally non‐atherogenic, enhances the migration of Mφ and accelerates the foam cell formation. We first demonstrated that extracellular ATP at 2–7.5 mM markedly increased the formation and activation of NLRP3 inflammasomes in LPS‐primed bone marrow macrophages (BMMs) from wild type mice, which was confirmed by colocalization of NLRP3, ASC and caspase‐1, activation of caspase‐1, and enhanced IL‐1β production. In BMMs from ASC −/− mice, the formation and activation of NLRP3 inflammasomes in Mφ were substantially attenuated. By oil red staining, ASC +/+ BMMs were found to have dramatic lipids accumulation after ATP pretreatment. Further confocal microscopic analysis of colocalization of filipin‐stained intracellular cholesterol and lysosomal marker Lamp‐1 demonstrated that large amount of cholesterol was accumulated in lysosomes of ASC +/+ BMMs pretreated by ATP, which was not observed in ASC −/− BMMS. In addition, ATP‐induced NLRP3 inflammasomes activation increased migration of ASC +/+ BMMS, which was markedly attenuated in ASC −/− BMMs. However, the effects of ATP on Mφ migration were not dependent on IL‐1β. These results suggest that activation of NLRP3 inflammasomes even by non‐atherogenic stimuli also remarkably increases the susceptibility of Mφ to lipid deposition and their migration ability, which may result in migration of Mφ into arterial wall, where they form foam cells and ultimately induce atherosclerosis (supported by NIH grants HL057244, HL091464 and HL075316).