Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis

Moritz Leppkes (), Christian Maueröder, Sebastian Hirth, Stefanie Nowecki, Claudia Günther, Ulrike Billmeier, Susanne Paulus, Mona Biermann, Luis E. Munoz, Markus Hoffmann, Dane Wildner, Andrew L. Croxford, Ari Waisman, Kerri Mowen, Dieter E. Jenne, Veit Krenn, Julia Mayerle, Markus M. Lerch, Georg Schett, Stefan Wirtz, Markus F. Neurath, Martin Herrmann and Christoph Becker
Additional contact information
Moritz Leppkes: University Clinics Erlangen, University of Erlangen-Nuremberg
Christian Maueröder: University Clinics Erlangen, University of Erlangen-Nuremberg
Sebastian Hirth: Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University
Stefanie Nowecki: University Clinics Erlangen, University of Erlangen-Nuremberg
Claudia Günther: University Clinics Erlangen, University of Erlangen-Nuremberg
Ulrike Billmeier: University Clinics Erlangen, University of Erlangen-Nuremberg
Susanne Paulus: University Clinics Erlangen, University of Erlangen-Nuremberg
Mona Biermann: University Clinics Erlangen, University of Erlangen-Nuremberg
Luis E. Munoz: University Clinics Erlangen, University of Erlangen-Nuremberg
Markus Hoffmann: University Clinics Erlangen, University of Erlangen-Nuremberg
Dane Wildner: University Clinics Erlangen, University of Erlangen-Nuremberg
Andrew L. Croxford: Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University
Ari Waisman: Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University
Kerri Mowen: Scripps Institute
Dieter E. Jenne: Institute of Lung Biology and Disease, Comprehensive Pneumology Center
Veit Krenn: MVZ of Pathology
Julia Mayerle: University Medicine Greifswald
Markus M. Lerch: University Medicine Greifswald
Georg Schett: University Clinics Erlangen, University of Erlangen-Nuremberg
Stefan Wirtz: University Clinics Erlangen, University of Erlangen-Nuremberg
Markus F. Neurath: University Clinics Erlangen, University of Erlangen-Nuremberg
Martin Herrmann: University Clinics Erlangen, University of Erlangen-Nuremberg
Christoph Becker: University Clinics Erlangen, University of Erlangen-Nuremberg

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10973

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