Immunity
Volume 51, Issue 3, 17 September 2019, Pages 443-450.e4
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Neutrophil Extracellular Traps Initiate Gallstone Formation

https://doi.org/10.1016/j.immuni.2019.07.002Get rights and content
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Highlights

  • Gallstones contain extracellular DNA and neutrophil-derived granular enzymes

  • Neutrophils form extended aggregates of gallstone building blocks in vitro

  • Uptake of crystals by neutrophils causes lysosomal leakage and NET formation

  • NOX2 and PADI4 activities are required for the generation and growth of gallstones

Summary

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.

Keywords

neutrophils
gallstones
neutrophil extracellular traps
cholesterol crystals
calcium carbonate crystals
lisosomal leakage
NOX2
PADi4
gallstone growth
lithogenic diet

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10

These authors contributed equally

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