The Nalp3 inflammasome is essential for the development of silicosis

Our plain-English summary of The Nalp3 inflammasome is essential for the development of silicosis, by S.L. Cassel, S.C. Eisenbarth, S.S. Iyer, et al (Proceedings of the National Academy of Sciences of the United States of America, 2008).

The study

• Authors: S.L. Cassel, S.C. Eisenbarth, S.S. Iyer, J.J. Sadler, O.R. Colegio, L.A. Tephly, A.B. Carter, P.B. Rothman, R.A. Flavell, F.S. Sutterwala
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2008;105(26):9035-40
• Cited by: 710 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1beta and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.

In plain English

This laboratory study used mouse cells, human lung cells and mice to examine how silica and asbestos set off lung inflammation. The authors first 'primed' macrophages (immune cells) with a bacterial substance (LPS), then exposed them to crystalline silica, crocidolite asbestos or titanium dioxide. Primed mouse macrophages released the inflammatory signal IL-1 beta in response to silica and asbestos, but not titanium dioxide. Primed alveolar macrophages from normal human volunteers also released IL-1 beta in response to silica or asbestos. Mouse macrophages lacking Nalp3, part of a protein complex called an inflammasome, had a marked defect in releasing IL-1 beta in response to silica. Asbestos-triggered IL-1 beta release also depended on Nalp3. For silica, this response needed potassium to leave the cell and needed reactive oxygen species. Mice were given silica into the nose on days 0 and 14. Three months later, mice lacking Nalp3 or its partner protein ASC had less lung inflammation and less collagen (scarring) than normal mice. Asbestos was tested only in cells, not in living mice. The authors concluded that activation of Nalp3 by silica is instrumental in the development of silicosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiments: cell-culture (in vitro) studies of mouse and human macrophages, plus an animal experiment (mouse model of silicosis)
• Who was studied: Macrophages from normal (C57BL/6) mice and from mice lacking Nalp3, ASC, caspase-1 or IPAF. Alveolar macrophages from normal human volunteers. In the animal experiment, normal, ASC-deficient and Nalp3-deficient mice: five mice per group received silica and two per group received saline (PBS).
• Exposure: Crystalline silica (Min-U-Sil-5), crocidolite asbestos from the North American Insulation Manufacturers Association Fiber Repository, and titanium dioxide as a comparison particle, applied to cultured macrophages. In mice, only silica was given, by instillation into the nose on days 0 and 14.
• Main results:
  • Primed normal mouse macrophages released IL-1 beta when treated with asbestos, and the amount rose with the dose.
  • Titanium dioxide did not cause primed mouse macrophages to release IL-1 beta.
  • Primed alveolar macrophages from normal human volunteers released IL-1 beta in response to silica or asbestos.
  • Primed mouse macrophages lacking Nalp3, ASC or caspase-1 had a marked defect in releasing IL-1 beta in response to silica, compared with normal macrophages. Asbestos-induced IL-1 beta release in normal macrophages was also Nalp3-dependent.
  • Silica killed cells to an equal degree in normal and Nalp3-deficient macrophages.
  • Raising potassium outside the cells significantly reduced silica-induced IL-1 beta release.
  • The ROS inhibitor DPI markedly reduced silica-induced IL-1 beta release and caspase-1 activation.
  • Three months after silica instillation, ASC- and Nalp3-deficient mice showed less lung inflammation and granuloma formation than normal mice.
  • After silica, ASC- and Nalp3-deficient mice had less collagen deposition (scarring) in the lungs than normal mice.
• The authors' conclusion: The authors concluded that activation of the Nalp3 inflammasome by silica is instrumental in the development of silicosis, and that macrophages directly recognize and react to silica through the Nalp3 inflammasome.
• Limitations the authors state:
  • The ROS experiments could not tell which of the two likely cellular sources produced the reactive oxygen species.
  • The cells needed priming before they responded to silica or asbestos, and the authors state that the source of this priming in the body is unclear.
  • The authors did not test whether the scavenger receptors SR-A and MARCO are needed for silica to activate Nalp3.

Topics

Medical terms in this study, explained in our Lexicon: Silicosis, Crystalline, Alveolar Macrophage, Pulmonary Fibrosis, Macrophage, Cytokine, Reactive Oxygen Species (ROS), Pneumoconiosis.

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