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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.
Nat. Commun. 7:10973 (2016)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Extracellular Trap Formation; Cathepsin-b; Mouse Model; Autoimmune Pancreatitis; Biliary Pancreatitis; Trypsin Activation; Tissue-damage; Lung Injury; In-vivo; Mice
ISSN (print) / ISBN
2041-1723
e-ISSN
2041-1723
Journal
Nature Communications
Quellenangaben
Volume: 7,
Article Number: 10973
Publisher
Springer
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)