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

<jats:p> Nanoparticles are increasingly used in various fields, including biomedicine and electronics. One application utilizes the opacifying effect of nano-TiO <jats:sub>2</jats:sub> , which is frequently used as pigment in cosmetics. Although TiO <jats:sub>2</jats:sub> is believed to be biologically inert, an emerging literature reports increased incidence of respiratory diseases in people exposed to TiO <jats:sub>2</jats:sub> . Here, we show that nano-TiO <jats:sub>2</jats:sub> and nano-SiO <jats:sub>2</jats:sub> , 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 <jats:sub>2</jats:sub> –dependent-Nlrp3 activity does not require cytoskeleton-dependent phagocytosis and induces IL-1α/β secretion in nonphagocytic keratinocytes. Inhalation of nano-TiO <jats:sub>2</jats:sub> provokes lung inflammation which is strongly suppressed in IL-1R– and IL-1α–deficient mice. Thus, the inflammation caused by nano-TiO <jats:sub>2</jats:sub> in vivo is largely caused by the biological effect of IL-1α. The current use of nano-TiO <jats:sub>2</jats:sub> may present a health hazard due to its capacity to induce IL-1R signaling, a situation reminiscent of inflammation provoked by asbestos exposure. </jats:p>