title: Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.
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.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Leppkes
authors.affiliation: Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maueröder
authors.affiliation: Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University, 55131 Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hirth
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nowecki
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Billmeier
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Paulus
authors.affiliation: Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Biermann
authors.affiliation: Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Luis E
authors.identifier: http://orcid.org/0000-0002-5395-804X
authors.initials: LE
authors.lastname: Munoz
authors.affiliation: Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Dane
authors.identifier: http://orcid.org/0000-0002-4916-6533
authors.initials: D
authors.lastname: Wildner
authors.affiliation: Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University, 55131 Mainz, Germany.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Croxford
authors.affiliation: Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University, 55131 Mainz, Germany.
authors.forename: Ari
authors.identifier: http://orcid.org/0000-0003-4304-8234
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Department of Chemical Physiology, Scripps Institute, La Jolla, California 92037, USA.|Department of Immunology and Microbial Sciences, Scripps Institute, La Jolla, California 92037, USA.
authors.forename: Kerri
authors.initials: K
authors.lastname: Mowen
authors.affiliation: Institute of Lung Biology and Disease, Comprehensive Pneumology Center, 81377 Munich, Germany.
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.affiliation: Department of Pathology, MVZ of Pathology, 54296 Trier, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Krenn
authors.affiliation: Department of Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: Department of Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D002843:Chromatin / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D065206:Extracellular Traps / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000494:pharmacology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010183:Pancreatic Ducts / Q000276:immunology* / Q000473:pathology; D010189:Pancreatic Juice / Q000201:enzymology / Q000276:immunology; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002843:Chromatin; D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D002108:Ceruletide; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse