Silica crystals and aluminum salts mediate NALP-3 inflammasome activation via phagosomal destabilization

By V. Hornung, F. Bauernfeind, A. Halle, Eivind Samstad, H. Kono, K. Rock, Katherine A. Fitzgerald, E. Latz. Nature Immunology, 2008

2,940 citations recorded by the source corpus.

Inhalation of silica crystals causes inflammation in the alveolar space. Prolonged exposure to silica 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 activated inflammasomes formed by the cytoplasmic receptor NALP3. NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. 'Sterile' lysosomal damage (without crystals) also induced NALP3 activation, and inhibition of either phagosomal acidification or cathepsin B activity impaired NALP3 activation. Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal.

Subfields: Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/31b80027789866f7a1a29b9a59b1be0335e7bb97

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In Molecular Biology

In Pediatrics, Perinatology and Child Health

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Citations in the corpus

Inflammasomes and their roles in health and disease. (2012, background): “In this regard, cathepsin B–mediated processing of a cytosolic factor was suggested to act upstream of Nlrp3 activation by silica, alum, and amyloid-β fibrils (Halle et al. 2008, Hornung et al. 2008).”
An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation (2020, background): “Consistent with this, another study reported the activation of NLRP3 inflammasome by silica crystals and aluminum salts via Nrf2 mediated phagocytosis [218].”
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NLRP3 inflammasome and its inhibitors: a review (2015, background): “…damage or dysfunction caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and…”
Inflammasomes in health and disease (2012, background): “These non-exclusive mechanisms include both direct and indirect signal recognition mediated by additional accessory protein”
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The sterile inflammatory response (2010, background): “Consistent with this hypothesis, macrophages in which cathepsin B was inhibited or genetically absent showed a partial but significant reduction in IL-1β production to particles but not to ATP(56, 99).”
Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation (2010, background): “The NLRP3 receptor can be activated by diverse agents, such as extracellular ATP [12], inhaled silica and asbestos [14,24], and endogenously formed monosodium urate crystals [15].”