Journal Article

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis

Hirth, Sebastian, Herrmann, Martin, Schett, Georg, Wirtz, Stefan, Mowen, Kerri, Günther, Claudia, Krenn, Veit, Biermann, Mona, Munoz, Luis E., Croxford, Andrew L., Nowecki, Stefanie, Becker, Christoph, Waisman, Ari, Hoffmann, Markus, Jenne, Dieter E., Paulus, Susanne, Maueröder, Christian, Wildner, Dane, Mayerle, Julia, Neurath, Markus F., Lerch, Markus M., Leppkes, Moritz, Billmeier, Ulrike

2016

Overview

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. Pancreatitis often develops as a consequence of ductal obstruction. Here, the authors show that bicarbonate ions initiate the release of neutrophil extracellular traps (NETs) that form pancreatic ductal aggregates and occlude the ducts, thereby driving pancreatitis in mice and humans.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/2 / 13/21 / 13/31 / 13/44 / 13/51 / 14/19 / 14/5 / 14/63 / 38 / 38/77 / 38/90 / 631/250/2504/223/1699 / 631/337/100 / 64/60 / 692/308 / 692/699/1503/1712/1714 / 96/34 / Aggregates / Animals / Calcium carbonate / Ceruletide - toxicity / Chromatin - immunology / Crystals / Cytokines - immunology / Disease Models, Animal / Extracellular Traps - immunology / Flow Cytometry / Humanities and Social Sciences / Humans / Hydrolases - metabolism / Immunohistochemistry / Interleukin-17 - pharmacology / Mice / multidisciplinary / Neutrophils - immunology / Pancreas - drug effects / Pancreas - immunology / Pancreas - pathology / Pancreatic Ducts - immunology / Pancreatic Ducts - pathology / Pancreatic Juice - enzymology / Pancreatic Juice - immunology / Pancreatitis - chemically induced / Pancreatitis - immunology / Pancreatitis - pathology / Protein-Arginine Deiminases / Reverse Transcriptase Polymerase Chain Reaction / Science / Science (multidisciplinary)