6533b831fe1ef96bd12984ec
RESEARCH PRODUCT
Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis
Dane WildnerStefan WirtzSusanne PaulusLuis E. MuñozMartin HerrmannGeorg SchettChristian MaueröderStefanie NoweckiAri WaismanAndrew L. CroxfordAndrew L. CroxfordJulia MayerleClaudia GüntherMarkus M. LerchVeit KrennMona H C BiermannChristoph BeckerDieter E. JenneUlrike BillmeierKerri A. MowenSebastian HirthMarkus F. NeurathMoritz LeppkesMarkus H. Hoffmannsubject
0301 basic medicineExtracellular TrapsHydrolasesNeutrophilsScienceGeneral Physics and AstronomyBiologyExtracellular TrapsArticleGeneral Biochemistry Genetics and Molecular BiologyMice03 medical and health sciencesPancreatic JuiceProtein-Arginine Deiminase Type 4medicineAnimalsHumansPancreasCeruletideMultidisciplinaryReverse Transcriptase Polymerase Chain ReactionQInterleukin-17Pancreatic DuctsGeneral ChemistryNeutrophil extracellular trapsFlow Cytometrymedicine.diseaseImmunohistochemistryChromatinCell biologyChromatinDisease Models AnimalHistone citrullination030104 developmental biologymedicine.anatomical_structurePancreatitisChronic DiseasePancreatic juiceImmunologyProtein-Arginine DeiminasesCytokinesPancreatitisPancreasCeruletidedescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-03-01 | Nature Communications |