Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones

Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Otolaryngology, Head and Neck Surgery, Universitätsklinikum Erlangen, Waldstrasse 1, 91054 Erlangen, Germany

Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany

Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Deutsches Zentrum für Immuntherapie, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany

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Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Institute of Functional and Clinical Anatomy, Universitätsstrasse 19, 91054 Erlangen, Germany

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Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

These authors contributed equally to this work.

Cells 2020, 9(9), 2139; https://doi.org/10.3390/cells9092139

Received: 27 August 2020 / Revised: 13 September 2020 / Accepted: 16 September 2020 / Published: 22 September 2020

(This article belongs to the Special Issue NET Formation in Health and Disease)

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Abstract

Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth. View Full-Text

Keywords: sialolithiasis; salivary stones; lithogenesis; stone development; stone growth; sialadenitis; salivary glands; neutrophils; neutrophil extracellular traps

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Supplementary File 1:
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Doi: 10.21203/rs.3.rs-47256/v1
Link: https://www.researchsquare.com/article/rs-47256/v1
Description: Figure 1 S (supplement). The center of the sialolith with a strong autofluorescence, discriminating the core from the outer layers. Representative LSFM (Light sheet fluorescence microscopy) of a submandibular sialolith (n = 3). After decalcification, the strong central autofluorescence separated the core from the outer layers. Scale bar: 10 mm.
Externally hosted supplementary file 2
Doi: 10.21203/rs.3.rs-47256/v1
Link: https://www.researchsquare.com/article/rs-47256/v1
Description: N/A

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MDPI and ACS Style

Schapher, M.; Koch, M.; Weidner, D.; Scholz, M.; Wirtz, S.; Mahajan, A.; Herrmann, I.; Singh, J.; Knopf, J.; Leppkes, M.; Schauer, C.; Grüneboom, A.; Alexiou, C.; Schett, G.; Iro, H.; Muñoz, L.E.; Herrmann, M. Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones. Cells 2020, 9, 2139. https://doi.org/10.3390/cells9092139

AMA Style

Schapher M, Koch M, Weidner D, Scholz M, Wirtz S, Mahajan A, Herrmann I, Singh J, Knopf J, Leppkes M, Schauer C, Grüneboom A, Alexiou C, Schett G, Iro H, Muñoz LE, Herrmann M. Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones. Cells. 2020; 9(9):2139. https://doi.org/10.3390/cells9092139

Chicago/Turabian Style

Schapher, Mirco, Michael Koch, Daniela Weidner, Michael Scholz, Stefan Wirtz, Aparna Mahajan, Irmgard Herrmann, Jeeshan Singh, Jasmin Knopf, Moritz Leppkes, Christine Schauer, Anika Grüneboom, Christoph Alexiou, Georg Schett, Heinrich Iro, Luis E. Muñoz, and Martin Herrmann. 2020. "Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones" Cells 9, no. 9: 2139. https://doi.org/10.3390/cells9092139

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Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones

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