| Summary: | 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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