Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β

Our plain-English summary of Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β, by A.S. Yazdi, G. Guarda, N. Riteau, et al (Proceedings of the National Academy of Sciences of the United States of America, 2010).

The study

• Authors: A.S. Yazdi, G. Guarda, N. Riteau, S.K. Drexler, A. Tardivel, I. Couillin, J. Tschopp
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2010;107(45):19449-54
• Cited by: 405 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Nanoparticles are increasingly used in various fields, including biomedicine and electronics. One application utilizes the opacifying effect of nano-TiO(2), which is frequently used as pigment in cosmetics. Although TiO(2) is believed to be biologically inert, an emerging literature reports increased incidence of respiratory diseases in people exposed to TiO(2). Here, we show that nano-TiO(2) and nano-SiO(2), but not nano-ZnO, activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome, leading to IL-1β release and in addition, induce the regulated release of IL-1α. Unlike other particulate Nlrp3 agonists, nano-TiO(2)-dependent-Nlrp3 activity does not require cytoskeleton-dependent phagocytosis and induces IL-1α/β secretion in nonphagocytic keratinocytes. Inhalation of nano-TiO(2) provokes lung inflammation which is strongly suppressed in IL-1R- and IL-1α-deficient mice. Thus, the inflammation caused by nano-TiO(2) in vivo is largely caused by the biological effect of IL-1α. The current use of nano-TiO(2) may present a health hazard due to its capacity to induce IL-1R signaling, a situation reminiscent of inflammation provoked by asbestos exposure.

In plain English

This was a laboratory study combining cell experiments with mouse experiments, testing whether metal-oxide nanoparticles trigger the Nlrp3 inflammasome. In human THP1 macrophages stimulated for 6 h, TiO2 (anatase 20 nm and rutile 80 nm) and SiO2 (15 nm) induced caspase-1 cleavage and IL-1 beta release, while ZnO (15 nm) did not. Primary human keratinocytes released mature IL-1 beta after nano-TiO2 and nano-SiO2 but not after carbon nanotubes. IL-1 beta release was abolished in THP1 cells with shRNA against caspase-1 or Nlrp3 and in ASC- or Nlrp3-deficient mouse dendritic cells, but not with Nlrc4/IPAF loss. Blocking actin-dependent phagocytosis with cytochalasin D did not stop TiO2-induced IL-1 beta secretion. In mice, intranasal nano-TiO2 caused neutrophil influx into bronchoalveolar lavage fluid that was significantly reduced by IL-1R, caspase-1, ASC and IL-1 alpha deficiency, while Nlrp3 dependence did not reach significance. After one skin application, 8/11 (72%) TiO2-treated mice showed acanthosis without inflammatory infiltrate and 2/11 (18%) PBS-treated mice showed epidermal alterations; the authors noted this thickening might reflect mechanical irritation from scratching or licking. The authors concluded nano-TiO2 acts via IL-1R signalling, resembling inflammation provoked by asbestos.

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: Experimental laboratory study: in vitro human and mouse cell culture plus in vivo mouse peritonitis, skin and intranasal exposure models
• Who was studied: Human THP1 macrophage cell line, primary human keratinocytes (neonatal foreskin), mouse bone marrow-derived dendritic cells and macrophages, primary murine keratinocytes, and knockout mice (Nlrp3-/-, Asc-/-, Ipaf-/-, IL-1 alpha, IL-1R-/-, caspase-1-/-) aged 6-10 weeks, at Lausanne (Switzerland) and Orleans (France); 7-10 mice per group in peritonitis, 6-8 per group in lung experiments
• Exposure: Engineered nanoparticles: TiO2 anatase 20 nm, TiO2 rutile 80 nm, ZnO 15 nm, SiO2 15 nm, carbon nanotubes, plus micrometre-sized SiO2 (1.5 micrometres) and MSU as comparison; in vitro mostly 200 micrograms per mL, in vivo 1-1.5 mg i.p. or 7.5-30 mg/kg intranasally
• Main results:
  • In human THP1 macrophages, TiO2 (20 nm and 80 nm) and SiO2 (15 nm) induced caspase-1 cleavage and IL-1 beta secretion, whereas ZnO (15 nm) did not
  • Primary human keratinocytes released mature IL-1 beta dose-dependently after nano-TiO2 and nano-SiO2, but not after carbon nanotubes
  • IL-1 beta release depended on the Nlrp3 inflammasome (knockdown in THP1 cells; ASC- or Nlrp3-deficient mouse dendritic cells) but not on IPAF/Nlrc4
  • Blocking actin-dependent phagocytosis with cytochalasin D did not suppress nanoparticle-induced IL-1 beta secretion in macrophages
  • After i.p. injection in mice, nano-TiO2-induced peritonitis depended on the ASC adapter, while Nlrp3 deficiency alone did not significantly affect it
  • A single intranasal dose of nano-TiO2 caused neutrophil influx into bronchoalveolar lavage fluid, significantly blocked by IL-1R or caspase-1 deficiency
  • In the lung model neutrophil influx depended significantly on ASC and highly on IL-1 alpha, with only partial, non-significant dependence on Nlrp3
  • In bronchoalveolar lavage fluid, TiO2 produced a prominent increase of IL-1 beta and IL-6, with only minor IL-1 alpha and TNF
  • After a single skin application of TiO2, 8/11 (72%) mice showed acanthosis without inflammatory infiltrate, while 2/11 (18%) PBS-treated mice showed epidermal alterations
• The authors' conclusion: The authors concluded that nano-TiO2 shows IL-1R-dependent proinflammatory activity in lung and peritoneum, with IL-1 alpha dominating over IL-1 beta/Nlrp3, and drew a parallel with asbestos-induced inflammation
• Limitations the authors state:
  • The authors state the exact mechanism of nano-TiO2 uptake into cells remains unknown
  • The authors note that the dominant effect of IL-1 alpha in the lung model may mask a contribution of IL-1 beta/Nlrp3
  • The authors note the skin epidermal thickening seen after TiO2 may be due to mechanical irritation from mice scratching or licking rather than the particles themselves

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Phagocytosis, Asbestos Exposure.

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