Amorphous silica particles, such as nanoparticles (<100 nm diameter particles), are used in a wide variety of products, including pharmaceuticals, paints, cosmetics, and food. Nevertheless, the immunotoxicity of these particles and the relationship between silica particle size and pro-inflammatory activity are not fully understood. In this study, we addressed the relationship between the size of amorphous silica (particle dose, diameter, number, and surface area) and the inflammatory activity (macrophage phagocytosis, inflammasome activation, IL-1β secretion, cell death and lung inflammation). Irrespective of diameter size, silica particles were efficiently internalized by mouse bone marrow-derived macrophages via an actin cytoskeleton-dependent pathway, and induced caspase-1, but not caspase-11, activation. Of note, 30 nm-1000 nm diameter silica particles induced lysosomal destabilization, cell death, and IL-1β secretion at markedly higher levels than did 3000 nm-10000 nm silica particles. Consistent with in vitro results, intra-tracheal administration of 30 nm silica particles into mice caused more severe lung inflammation than that of 3000 nm silica particles, as assessed by measurement of pro-inflammatory cytokines and neutrophil infiltration in bronchoalveolar lavage fluid of mice, and by the micro-computed tomography analysis. Taken together, these results suggest that silica particle size impacts immune responses, with submicron amorphous silica particles inducing higher inflammatory responses than silica particles over 1000 nm in size, which is ascribed not only to their ability to induce caspase-1 activation but also to their cytotoxicity.
WHO (2007) The Global Occupational Health Network newsletter: elimination of silicosis. http://www.who.int/occupational_health/p?ublications/newsletter/gohnet12e.pdf. Issue No. 12 – 2007
[3]
Bowman DM, van Calster G, Friedrichs S (2010) Nanomaterials and regulation of cosmetics. Nat Nanotechnol 5: 92–92. doi: 10.1038/nnano.2010.12
[4]
Kaewamatawong T, Kawamura N, Okajima M, Sawada M, Morita T, et al. (2005) Acute pulmonary toxicity caused by exposure to colloidal silica: Particle size dependent pathological changes in mice. Toxicol Pathol 33: 743–749. doi: 10.1080/01926230500416302
[5]
Cho W-S, Choi M, Han BS, Cho M, Oh J, et al. (2007) Inflammatory mediators induced by intratracheal instillation of ultrafine amorphous silica particles. Toxicol Lett 175: 24–33. doi: 10.1016/j.toxlet.2007.09.008
[6]
Costantini LM, Gilberti RM, Knecht DA (2011) The Phagocytosis and Toxicity of Amorphous Silica. Plos One 6(2): e14647. doi: 10.1371/journal.pone.0014647
[7]
Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, et al. (2010) Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1 alpha and IL-1 beta. Proc Natl Acad Sci U S A 107: 19449–19454. doi: 10.1073/pnas.1008155107
[8]
Hirai T, Yoshikawa T, Nabeshi H, Yoshida T, Tochigi S, et al. (2012) Amorphous silica nanoparticles size-dependently aggravate atopic dermatitis-like skin lesions following an intradermal injection. Part Fibre Toxicol 9: 3. doi: 10.1186/1743-8977-9-3
[9]
Morishige T, Yoshioka Y, Inakura H, Tanabe A, Yao XL, et al. (2010) The effect of surface modification of amorphous silica particles on NLRP3 inflammasome mediated IL-1 beta production, ROS production and endosomal rupture. Biomaterials 31: 6833–6842. doi: 10.1016/j.biomaterials.2010.05.036
[10]
Morishige T, Yoshioka Y, Inakura H, Tanabe A, Narimatsu S, et al. (2012) Suppression of nanosilica particle-induced inflammation by surface modification of the particles. Arch Toxicol 86: 1297–1307. doi: 10.1007/s00204-012-0823-5
[11]
Waters KM, Masiello LM, Zangar RC, Karin NJ, Quesenberry RD, et al. (2009) Macrophage Responses to Silica Nanoparticles are Highly Conserved Across Particle Sizes. Toxicol Sci 107: 553–569. doi: 10.1093/toxsci/kfn250
[12]
Srivastava KD, Rom WN, Jagirdar J, Yie TA, Gordon T, et al. (2002) Crucial role of interleukin-1 beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice. Am J Respir Crit Care Med 165: 527–533. doi: 10.1164/ajrccm.165.4.2106009
[13]
Gasse P, Mary C, Guenon I, Noulin N, Charron S, et al. (2007) IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest 117: 3786–3799. doi: 10.1172/jci32285
Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, et al. (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320: 674–677. doi: 10.1126/science.1156995
[16]
Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, et al. (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9: 847–856. doi: 10.1038/ni.1631
[17]
Nakayama M, Underhill DM, Petersen TW, Li B, Kitamura T, et al. (2007) Paired Ig-like receptors bind to bacteria and shape TLR-mediated cytokine production. J Immunol 178: 4250–4259. doi: 10.4049/jimmunol.178.7.4250
[18]
Nakayama M, Kurokawa K, Nakamura K, Lee BL, Sekimizu K, et al. (2012) Inhibitory Receptor Paired Ig-like Receptor B Is Exploited by Staphylococcus aureus for Virulence. J Immunol 189: 5903–5911. doi: 10.4049/jimmunol.1201940
[19]
Sandberg WJ, Lag M, Holme JA, Friede B, Gualtieri M, et al. (2012) Comparison of non-crystalline silica nanoparticles in IL-1 beta release from macrophages. Part Fibre Toxicol 9: 32. doi: 10.1186/1743-8977-9-32
[20]
Nabeshi H, Yoshikawa T, Matsuyama K, Nakazato Y, Tochigi S, et al. (2011) Amorphous nanosilica induce endocytosis-dependent ROS generation and DNA damage in human keratinocytes. Part Fibre Toxicol 8: 1. doi: 10.1186/1743-8977-8-1
[21]
Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, et al. (2008) The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A 105: 9035–9040. doi: 10.1073/pnas.0803933105
[22]
Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, et al. (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479: 117–121. doi: 10.1038/nature10558
[23]
Kang SJ, Wang SY, Hara H, Peterson EP, Namura S, et al. (2000) Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol 149: 613–622. doi: 10.1083/jcb.149.3.613
[24]
Wang SY, Miura M, Jung YK, Zhu H, Gagliardini V, et al. (1996) Identification and characterization of Ich-3, a member of the interleukin-1 beta converting enzyme (ICE)/Ced-3 family and an upstream regulator of ICE. J Biol Chem 271: 20580–20587. doi: 10.1074/jbc.271.34.20580
[25]
Miao EA, Rajan JV, Aderem A (2011) Caspase-1-induced pyroptotic cell death. Immunol Rev 243: 206–214. doi: 10.1111/j.1600-065x.2011.01044.x
[26]
Choi M, Cho WS, Han BS, Cho MJ, Kim S, et al. (2008) Transient pulmonary fibrogenic effect induced by intratracheal instillation of ultrafine amorphous silica in A/J mice. Toxicol Lett 182: 97–101. doi: 10.1016/j.toxlet.2008.08.019
[27]
Hamilton RF, Thakur SA, Mayfair JK, Holian A (2006) MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice. J Biol Chem 281: 34218–34226. doi: 10.1074/jbc.m605229200
[28]
Brown JM, Swindle EJ, Kushnir-Sukhov NM, Holian A, Metcalfe DD (2007) Silica-directed mast cell activation is enhanced by scavenger receptors. Am J Respir Cell Mol Biol 36: 43–52. doi: 10.1165/rcmb.2006-0197oc
[29]
Mukhopadhyay S, Varin A, Chen YY, Liu BY, Tryggvason K, et al. (2011) SR-A/MARCO-mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens. Blood 117: 1319–1328. doi: 10.1182/blood-2010-03-276733
[30]
Dostert C, Guarda G, Romero JF, Menu P, Gross O, et al. (2009) Malarial hemozoin is a Nalp3 inflammasome activating danger signal. Plos One 4(8): e6510. doi: 10.1371/journal.pone.0006510
[31]
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cell explosion. Nat Rev Mol Cell Biol 20, 700–714. doi: 10.1038/nrm2970
[32]
De Jong WH, Hagens WI, Krystek P, Burger MC, Sips A, et al. (2008) Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29: 1912–1919. doi: 10.1016/j.biomaterials.2007.12.037
[33]
Nabeshi H, Yoshikawa T, Matsuyama K, Nakazato Y, Matsuo K, et al. (2011) Systemic distribution, nuclear entry and cytotoxicity of amorphous nanosilica following topical application. Biomaterials 32: 2713–2724. doi: 10.1016/j.biomaterials.2010.12.042
[34]
Nabeshi H, Yoshikawa T, Matsuyama K, Nakazato Y, Arimori A, et al. (2012) Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure. Nanotechnology 23. doi: 10.1088/0957-4484/23/4/045101
[35]
Aderem A, Underhill DM (1999) Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17: 593–623. doi: 10.1146/annurev.immunol.17.1.593