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Leppkes, M.* ; Maueroeder, C.* ; Hirth, S.* ; Nowecki, S.* ; Guenther, C.* ; Billmeier, U.* ; Paulus, S.* ; Biermann, M.* ; Munoz, L.E.* ; Hoffmann, M.* ; Wildner, D.* ; Croxford, A.L.* ; Waisman, A.* ; Mowen, K.* ; Jenne, D.* ; Krenn, V.* ; Mayerle, J.* ; Lerch, M.M.* ; Schett, G.* ; Wirtz, S.* ; Neurath, M.F.* ; Hermann, M.* ; Becker, C.*

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

Nat. Commun. 7:10973 (2016)
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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
Language english
Publication Year 2016
HGF-reported in Year 0
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 7, Issue: , Pages: , Article Number: 10973 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-501600-005
DOI 10.1038/ncomms10973
WOS ID WOS:000372019600001
Erfassungsdatum 2016-04-02
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