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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903678/ https://www.ncbi.nlm.nih.gov/pubmed/24475307 http://dx.doi.org/10.1371/journal.pone.0087552 |
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author | Li, Xiang Zhang, Yang Xia, Min Gulbins, Erich Boini, Krishna M. Li, Pin-Lan |
author_facet | Li, Xiang Zhang, Yang Xia, Min Gulbins, Erich Boini, Krishna M. Li, Pin-Lan |
author_sort | Li, Xiang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3903678 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39036782014-01-28 Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis Li, Xiang Zhang, Yang Xia, Min Gulbins, Erich Boini, Krishna M. Li, Pin-Lan PLoS One Research Article 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. Public Library of Science 2014-01-27 /pmc/articles/PMC3903678/ /pubmed/24475307 http://dx.doi.org/10.1371/journal.pone.0087552 Text en © 2014 Li et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Li, Xiang Zhang, Yang Xia, Min Gulbins, Erich Boini, Krishna M. Li, Pin-Lan Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis |
title | Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis |
title_full | Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis |
title_fullStr | Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis |
title_full_unstemmed | Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis |
title_short | Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implication of a Novel Role of Inflammasome in Atherogenesis |
title_sort | activation of nlrp3 inflammasomes enhances macrophage lipid-deposition and migration: implication of a novel role of inflammasome in atherogenesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903678/ https://www.ncbi.nlm.nih.gov/pubmed/24475307 http://dx.doi.org/10.1371/journal.pone.0087552 |
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