Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis

Leppkes M, Maueröder C, Hirth S, Nowecki S, Günther C, Billmeier U, Paulus S, Biermann M, Munoz LE, Hoffmann M, Wildner D, Croxford AL, Waisman A, Mowen K, Jenne DE, Krenn V, Mayerle J, Lerch MM, Schett G, Wirtz S, Neurath M, Herrmann M, Becker C (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 7

Pages Range: 10973

DOI: 10.1038/ncomms10973

Abstract

Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.

Authors with CRIS profile

Christian Maueröder Department of Medicine 3 – Rheumatology and Immunology Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Mona Biermann Lehrstuhl für Biochemie und Molekulare Medizin Luis Munoz Becerra Department of Medicine 3 – Rheumatology and Immunology Markus Hoffmann Department of Medicine 3 – Rheumatology and Immunology Dane Wildner Medizinische Fakultät Georg Schett Lehrstuhl für Innere Medizin III Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I Martin Herrmann Department of Medicine 3 – Rheumatology and Immunology Christoph Becker Professur für Molekulare Gastroenterologie

Involved external institutions

Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) Scripps Research Institute (TSRI) US United States (USA) (US) Medizinisches Versorgungszentrum der überörtlichen Berufsausübungsgemeinschaft für Histologie, Zytologie und Molekulare Diagnostik in Trier - Düren - Düsseldorf DE Germany (DE) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald DE Germany (DE)

How to cite

APA:

Leppkes, M., Maueröder, C., Hirth, S., Nowecki, S., Günther, C., Billmeier, U.,... Becker, C. (2016). Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nature Communications, 7, 10973. https://doi.org/10.1038/ncomms10973

MLA:

Leppkes, Moritz, et al. "Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis." Nature Communications 7 (2016): 10973.

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