Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica

Our plain-English summary of Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica, by C. Dostert, V. Pétrilli, R. Van Bruggen, et al (Science, 2008).

The study

• Authors: C. Dostert, V. Pétrilli, R. Van Bruggen, C. Steele, B.T. Mossman, J. Tschopp
• Journal: Science
• Published: 2008;320(5876):674-7
• Cited by: 2,128 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The inhalation of airborne pollutants, such as asbestos or silica, is linked to inflammation of the lung, fibrosis, and lung cancer. How the presence of pathogenic dust is recognized and how chronic inflammatory diseases are triggered are poorly understood. Here, we show that asbestos and silica are sensed by the Nalp3 inflammasome, whose subsequent activation leads to interleukin-1beta secretion. Inflammasome activation is triggered by reactive oxygen species, which are generated by a NADPH oxidase upon particle phagocytosis. (NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate.) In a model of asbestos inhalation, Nalp3-/- mice showed diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production. Our findings implicate the Nalp3 inflammasome in particulate matter-related pulmonary diseases and support its role as a major proinflammatory "danger" receptor.

In plain English

This laboratory study used cells and mice, not people. The authors tested whether asbestos and silica activate the Nalp3 inflammasome, an immune-cell protein complex that releases the inflammatory signal interleukin-1beta (IL-1beta). Human macrophage-like cells (THP1) and primary human macrophages released mature IL-1beta when exposed to asbestos or silica. In THP1 cells, diesel exhaust particles and cigarette smoke extract produced no detectable IL-1beta after 6 hours; diesel exhaust particles also produced none in primary macrophages. Reducing Nalp3, ASC or caspase-1 in the cells greatly reduced this release, and mouse macrophages lacking Nalp3 or ASC no longer processed and released it. The response depended on the cells trying to engulf the fibers and on reactive oxygen species from an NADPH oxidase. It was strongly reduced when iron on the fibers was chelated. Nalp3-deficient mice that inhaled chrysotile asbestos for 9 days had significantly fewer inflammatory cells in lung washings than normal littermates, and lower IL-1beta and KC. The authors concluded that the Nalp3 inflammasome is implicated in particle-related lung diseases. They suggested, without testing it, that the drug Anakinra might slow asbestosis and 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 on human and mouse immune cells (macrophages) in culture, plus an animal (mouse) asbestos inhalation experiment
• Who was studied: Human macrophage-like THP1 cells, primary human monocyte-derived macrophages, and macrophages from normal and gene-deficient mice. For the inhalation experiment, Nalp3-deficient (Nalp3-/-) mice and their normal (Nalp3+/+) littermates. The number of mice is not given in the text provided.
• Exposure: In cell experiments: asbestos (fiber type not stated in the text provided), silica, diesel exhaust particles, cigarette smoke extract (tested in THP1 cells) and monosodium urate crystals, for example 0.2 mg/ml asbestos for 6 hours. In mice: inhaled chrysotile asbestos for 9 days, with lungs analyzed on day 10, compared with air (sham) exposure.
• Main results:
  • THP1 cells released mature IL-1beta when exposed to asbestos or silica.
  • In THP1 cells, diesel exhaust particles and cigarette smoke extract did not produce detectable IL-1beta when measured after 6 hours.
  • Primary human monocyte-derived macrophages also produced mature IL-1beta after asbestos or silica, but not after diesel exhaust particles.
  • In THP1 cells in which Nalp3, ASC or caspase-1 had been knocked down, release of mature IL-1beta was highly reduced.
  • In macrophages from Nalp3-deficient and ASC-deficient mice, caspase-1 was no longer cleaved, and IL-1beta processing and release after asbestos, silica or MSU were abolished.
  • Blocking actin filaments with cytochalasin D, which interferes with the cells' attempt to engulf particles, inhibited IL-1beta release in response to asbestos.
  • Removing iron from the asbestos fibers (chelation with deferoxamine) strongly reduced IL-1beta maturation.
  • Knocking down the NADPH oxidase subunit p22phox in THP1 cells highly diminished IL-1beta release. Reactive oxygen species inhibitors also impaired IL-1beta production.
  • After 9 days of chrysotile asbestos inhalation, significantly fewer cells were recruited to the lungs (in bronchoalveolar lavage fluid) of Nalp3-/- mice than of normal mice.
  • In asbestos-exposed Nalp3-/- mice, lymphocyte, eosinophil and neutrophil infiltration was reduced, and IL-1beta and KC were decreased. IL-12(p40) production did not depend on Nalp3.
  • Mucin production was similarly increased by asbestos in both Nalp3-/- and normal lungs. However, significant increases in the number of mucin-producing distal bronchioles occurred in Nalp3-/- mice.
• The authors' conclusion: The authors concluded that their findings implicate the Nalp3 inflammasome in particulate matter-related lung diseases. They proposed that reactive oxygen species made by an NADPH oxidase are involved in its activation. They suggested that Anakinra, an IL-1 receptor antagonist drug, may be used to slow progression of asbestosis, silicosis and possibly other inflammatory lung diseases; this was not tested in the study.
• Limitations the authors state:
  • The authors stated that the IL-1beta release remaining in knocked-down cells was most likely due to incomplete shutdown of the targeted proteins.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Fibrosis, Lung Cancer, Reactive Oxygen Species (ROS), Phagocytosis, Cytokine.

Related studies

• The Nalp3 inflammasome is essential for the development of silicosis — S.L. Cassel, S.C. Eisenbarth, et al. (2008)
• Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation — L. Burton, D. Paget, et al. (2013)
• Vimentin regulates activation of the NLRP3 inflammasome — G. dos Santos, M.R. Rogel, et al. (2015)
• Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β — A.S. Yazdi, G. Guarda, et al. (2010)
• The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine — L. Baron, A. Gombault, et al. (2015)
• PKC/ROS-Mediated NLRP3 Inflammasome Activation Is Attenuated by Leishmania Zinc-Metalloprotease during Infection — M.T. Shio, J.G. Christian, et al. (2015)

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