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We have shown earlier that these particles induce activation of caspase-1 and secretion of IL-1\u03b2 by macrophages. However, whether the particles may produce other effects on immune cells is unclear. Here, we show that these particles induce the release of neutrophil extracellular traps (NETs) in a size-dependent manner by human neutrophils. Intracellular production of\u00a0reactive oxygen species is required for particle-induced NET release by neutrophils. NETs contain the high-mobility group protein B1 (HMGB1), a DNA-binding protein capable of inducing secretion of TNF-\u03b1 by a monocyte\/macrophage cell line and primary macrophages. HMGB1 functions as a ligand of Toll-like receptors 2 and 4 on macrophages, leading to activation of the MyD88 pathway and TNF-\u03b1 production. Furthermore, HMGB1 is critical to activate the particle-induced pro-inflammatory cascade in the peritoneum of mice. These results indicate that mineral particles promote pro-inflammatory responses by engaging neutrophils and macrophages via signaling of danger signals through NETs.<\/jats:p>","DOI":"10.1038\/s41598-017-16778-4","type":"journal-article","created":{"date-parts":[[2017,11,24]],"date-time":"2017-11-24T10:44:47Z","timestamp":1511520287000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Mineral particles stimulate innate immunity through neutrophil extracellular traps containing HMGB1"],"prefix":"10.1038","volume":"7","author":[{"given":"Hsin-Hsin","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ju","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Ojcius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiou-Mei","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren-Hao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Rong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Martel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,30]]},"reference":[{"key":"16778_CR1","doi-asserted-by":"publisher","first-page":"5549","DOI":"10.1073\/pnas.0711744105","volume":"105","author":"J Martel","year":"2008","unstructured":"Martel, J. & Young, J. D. Purported nanobacteria in human blood as calcium carbonate nanoparticles. Proc Natl Acad Sci USA \n                           105, 5549\u20135554 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"16778_CR2","doi-asserted-by":"publisher","first-page":"e8058","DOI":"10.1371\/journal.pone.0008058","volume":"4","author":"CY Wu","year":"2009","unstructured":"Wu, C. Y., Martel, J., Young, D. & Young, J. D. Fetuin-A\/albumin-mineral complexes resembling serum calcium granules and putative nanobacteria: demonstration of a dual inhibition-seeding concept. PLoS One \n                           4, e8058 (2009).","journal-title":"PLoS One"},{"key":"16778_CR3","doi-asserted-by":"publisher","first-page":"e5421","DOI":"10.1371\/journal.pone.0005421","volume":"4","author":"JD Young","year":"2009","unstructured":"Young, J. D. et al. Characterization of granulations of calcium and apatite in serum as pleomorphic mineralo-protein complexes and as precursors of putative nanobacteria. 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