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. 2010 Nov 9;107(45):19449-54.
doi: 10.1073/pnas.1008155107. Epub 2010 Oct 25.

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

Amir S Yazdi  1 , Greta Guarda, Nicolas Riteau, Stefan K Drexler, Aubry Tardivel, Isabelle Couillin, Jürg Tschopp
Affiliations

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

Amir S Yazdi et al. Proc Natl Acad Sci U S A. .

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. VSports手机版.

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The authors declare no conflict of interest.

VSports app下载 - Figures

Fig. 1.
Fig. 1.
Titanium and silica nanoparticles activate the Nlrp3 inflammasome in murine and human macrophages and human keratinocytes. (A) THP1 cells stimulated with MSU (300 μg/mL), TiO2 20 nm (200 μg/mL), TiO2 80 nm (200 μg/mL), SiO2 15 nm (200 μg/mL), and ZnO 15 nm (200 μg/mL) for 6 h and analyzed by Western blot. (B) Human primary keratinocytes stimulated with the indicated concentrations of TiO2, 20 nm, SiO2, 15 nm secreted IL-1β and cleaved caspase-1, whereas carbon nanotube exposure did not trigger caspase-1 cleavage. (C) Murine macrophages treated with MSU (300 μg/mL), nano-TiO2 (200 μg/mL), or nano-SiO2 (200 μg/mL) released IL-1β in an Nlrp3- and ASC-dependent manner. SN, supernatants; XT, cell extracts. Results are representative of three independent experiments.
Fig. 2.
Fig. 2.
Phagocytosis is not essential for nanoparticle-induced inflammasome activation. (A) Bone marrow-derived macrophages released IL-1β upon stimulation with MSU (300 μg/mL), TiO2 20 nm (200 μg/mL), TiO2 80 nm (200 μg/mL), SiO2 15 nm (200 μg/mL), and SiO2 1.5 μm (200 μg/mL). (B) In contrast, human keratinocytes released mature, cleaved IL-1β only upon exposure to nano-SiO2 (200 μg/mL) and not to μm-sized SiO2 (200 μg/mL). (C) Actin polymerization blockade by Cytochalasin D (1 μM) impaired MSU-induced inflammasome activation without affecting TiO2-dependent IL-1β secretion. Results are representative of three independent experiments. (D) TEM images of THP1 cells stimulated with nano-TiO2. TiO2 aggregates were free in the cytoplasm and not located in phagosomes.
Fig. 3.
Fig. 3.
Role of the inflammasome and IL-1α in murine models of TiO2-induced peritonitis and in murine BMDCs and primary murine keratinocytes. (A) I.p. injection of nano-TiO2 induced the recruitment of neutrophils to the peritoneal cavity. (B–F) The recruitment of inflammatory cells depended upon the presence of (B) IL-1R, (C) ASC, and (E) IL-1α, whereas the inflammatory response was only clearly dependent on Nlrp3 following IL-1α depletion (D and F). (*P < 0.05; **P < 0.01; ***P < 0.001; NS, nonsignificant, n = 7–10 mice per group). (G) Upon stimulation with MSU (300 μg/mL) or nano-TiO2 (200 μg/mL) release of IL-1β was completely abolished in Nlrp3- or ASC-deficient murine BMDCs, whereas the release of (H) IL-1α only partially depended on Nlrp3 and ASC. (I) Murine keratinocytes secreted IL-1α in a partially ASC-dependent manner upon stimulation with Nigericin (5 μM), nanoTiO2 (200 μg/mL), and nano-SiO2 (200 μg/mL), whereas exposure to nano-ZnO (200 μg/mL) did not trigger IL-1α secretion. Results are representative of three independent experiments.
Fig. 4.
Fig. 4.
Pulmonary exposure to TiO2. Intranasal application of nano-TiO2 triggered the recruitment of neutrophils to the bronchioalveolar fluid (BALF). Neutrophil recruitment was clearly dependent on (A) IL-1R, caspase-1, (B) ASC, and (C) IL-1α, whereas the recruitment did not significantly depend on Nlrp3. (D) Intranasal application of nano-TiO2 induced the secretion of IL-6 and IL-1β into the BALF, whereas TNF- and IL-1α production was only slightly increased. (E) In total lung tissue, significantly increased levels of IL-1α and IL-1β could be observed (*P < 0.05; **P < 0.01; ***P < 0.001; NS, nonsignificant; n = 6–8 mice per group).
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