2008
DOI: 10.1038/ni.1631
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Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization

Abstract: Inhalation of silica crystals causes inflammation in the alveolar space. Prolonged silica exposure can lead to the development of silicosis, an irreversible, fibrotic pulmonary disease. The mechanisms by which silica and other crystals activate immune cells are not well understood. Here, we demonstrate that silica and aluminum salt crystals activate the NALP3 inflammasome. NALP3 activation requires crystal phagocytosis and crystal uptake leads to lysosomal damage and rupture. Sterile lysosomal damage is also s… Show more

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Cited by 2,673 publications
(2,949 citation statements)
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References 39 publications
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“…When using LysoTracker Red to visualize lysosomes of BMDCs, separated fluorescence of APNs (green) and lysosomes (red) were observed, which suggested successful lysosomal escape and cytosolic delivery of APNs (Figure 2E). This was consistent with the earlier report that AlO(OH) can destabilize lysosomes 15. H2‐K b ‐SIINFEKL complexes on the surface of BMDCs were detected using the monoclonal antibody 25d1.16 and flow cytometry.…”
Section: Resultssupporting
confidence: 92%
“…When using LysoTracker Red to visualize lysosomes of BMDCs, separated fluorescence of APNs (green) and lysosomes (red) were observed, which suggested successful lysosomal escape and cytosolic delivery of APNs (Figure 2E). This was consistent with the earlier report that AlO(OH) can destabilize lysosomes 15. H2‐K b ‐SIINFEKL complexes on the surface of BMDCs were detected using the monoclonal antibody 25d1.16 and flow cytometry.…”
Section: Resultssupporting
confidence: 92%
“…34,46,47,49,54,56 Although ROS production is required for NLRP3 activation, several ROS-inducing agents do not promote inflammasome formation. 57,58 A third mechanism of NLRP3 activation proposed by Hornung and colleagues was that, in the case of large particulates, inflammasome activation occurs as a result of lysosomal swelling and leakage. 57 In contrast to the hypothesis of frustrated phagocytosis, this model proposes that upon cellular uptake silica and aluminum salts cause lysosome acidification with consequent release of acidic contents into the cytosol.…”
Section: Genetics Of the Inflammasomes In Human Pathologiesmentioning
confidence: 99%
“…57,58 A third mechanism of NLRP3 activation proposed by Hornung and colleagues was that, in the case of large particulates, inflammasome activation occurs as a result of lysosomal swelling and leakage. 57 In contrast to the hypothesis of frustrated phagocytosis, this model proposes that upon cellular uptake silica and aluminum salts cause lysosome acidification with consequent release of acidic contents into the cytosol. Indeed, inhibition of the lysosomal protease cathepsin B leads to a substantial decrease in activation of the NLRP3 inflammasome induced by silica.…”
Section: Genetics Of the Inflammasomes In Human Pathologiesmentioning
confidence: 99%
“…The following year, it was found that uric acid is induced by alum in vivo and is responsible for alum immunostimulatory properties, suggesting a possible, indirect involvement of the NLRP3 inflammasome [5], which can be activated by monosodium urate (MSU) crystals [12]. Shortly afterwards, five concomitant reports showed that alum-mediated caspase-1 activation in vitro was NLRP3 dependent [13][14][15][16][17], and also required ASC, the protein bridging NLRP3 and caspase-1 [13][14][15]17]. Caspase-1 is the enzyme responsible for the maturation and release of IL-1b and IL-18.…”
mentioning
confidence: 99%
“…It is worth noting that caspase-1 also participates in the secretion of IL-1a, biologically active without any need for proteolytic processing [18]. Alum activated NLRP3 directly upon phagocytosis [14,17] without any intermediary role for the danger signals MSU and ATP [14,15,17]. Furthermore, the involvement of the NLRC4 inflammasome was excluded [13,16,17].…”
mentioning
confidence: 99%