Neutrophil Extracellular Traps Initiate Gallstone Formation.
The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.
['Muñoz|Luis E|LE|', 'Boeltz|Sebastian|S|', 'Bilyy|Rostyslav|R|', 'Schauer|Christine|C|', 'Mahajan|Aparna|A|', 'Widulin|Navena|N|', 'Grüneboom|Anika|A|', 'Herrmann|Irmgard|I|', 'Boada|Edgyda|E|', 'Rauh|Manfred|M|', 'Krenn|Veit|V|', 'Biermann|Mona H C|MHC|', 'Podolska|Malgorzata J|MJ|', 'Hahn|Jonas|J|', 'Knopf|Jasmin|J|', 'Maueröder|Christian|C|', 'Paryzhak|Solomiya|S|', 'Dumych|Tetiana|T|', 'Zhao|Yi|Y|', 'Neurath|Markus F|MF|', 'Hoffmann|Markus H|MH|', 'Fuchs|Tobias A|TA|', 'Leppkes|Moritz|M|', 'Schett|Georg|G|', 'Herrmann|Martin|M|']
D000818:Animals D065206:Extracellular Traps D005260:Female D042882:Gallstones D006801:Humans D007113:Immunity, Innate D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D009504:Neutrophils D017382:Reactive Oxygen Species
neutrophil extracellular traps neutrophils gallstones NOX2 PADi4 calcium carbonate crystals cholesterol crystals gallstone growth lisosomal leakage lithogenic diet