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Sci Rep. 2017 Nov 30;7(1):16628. doi: 10.1038/s41598-017-16778-4.

Mineral particles stimulate innate immunity through neutrophil extracellular traps containing HMGB1.

Peng HH1,2,3,4, Liu YJ1,2, Ojcius DM2,5,6, Lee CM4, Chen RH7, Huang PR1,2,8, Martel J1,2,5, Young JD9,10,11,12,13.

Author information

1
Laboratory of Nanomaterials, Chang Gung University, Gueishan, Taoyuan, 33302, Taiwan.
2
Center for Molecular and Clinical Immunology, Chang Gung University, Gueishan, Taoyuan, 33302, Taiwan.
3
Department of Anesthesiology, Chang Gung Memorial Hospital, Gueishan, Taoyuan, 33305, Taiwan.
4
Laboratory Animal Center, Chang Gung Memorial Hospital, Gueishan, Taoyuan, 33305, Taiwan.
5
Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Gueishan, Taoyuan, 33305, Taiwan.
6
Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, 94103, USA.
7
Department of Medical Research and Development, Chang Gung Memorial Hospital, Gueishan, Taoyuan, 33305, Taiwan.
8
Department of Molecular and Cellular Biology, College of Medicine, Chang Gung University, Gueishan, Taoyuan, 33302, Taiwan.
9
Laboratory of Nanomaterials, Chang Gung University, Gueishan, Taoyuan, 33302, Taiwan. jdyoung@mail.cgu.edu.tw.
10
Center for Molecular and Clinical Immunology, Chang Gung University, Gueishan, Taoyuan, 33302, Taiwan. jdyoung@mail.cgu.edu.tw.
11
Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Gueishan, Taoyuan, 33305, Taiwan. jdyoung@mail.cgu.edu.tw.
12
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, 10021, USA. jdyoung@mail.cgu.edu.tw.
13
Biochemical Engineering Research Center, Ming Chi University of Technology, Taishan, New Taipei City 24301, Taiwan. jdyoung@mail.cgu.edu.tw.

Abstract

Calcium phosphate-based mineralo-organic particles form spontaneously in the body and may represent precursors of ectopic calcification. We have shown earlier that these particles induce activation of caspase-1 and secretion of IL-1β 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 reactive 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-α 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-α 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.

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