Neutrophil extracellular traps initiate gallstone formation
Gallstones are the most prevalent disease of the gallbladder and one of the leading causes of hospitalization worldwide. If the limit of solubilization capacity of the bile is reached, precipitation of bile components like cholesterol and calcium salts to crystals occurs. However, the factors and mechanism leading to the aggregation of these precipitations to larger gallstones are still not completely understood.
Prof. Martin Herrmann and his team from the University Hospital Erlangen in Germany revealed that chromatin, externalized by certain immune cells, plays a role in the aggregation of bile precipitations to gallstones.
Analysis of gallstones showed the presence of neutrophil-derived enzymes and extracellular DNA, indicating the interaction of gallstone components and neutrophil extracellular traps (NETs). The shell-like structure of gallstones suggests episodic growth, where calcium and cholesterol crystals aggregate during NET formation. Based on the fact that macropinocytosis is a key mechanism of NET formation, crystal uptake could be shown to cause lysosomal leakage, which results in decondensation and externalization of neutrophil DNA.
Furthermore, in vivo experiments in mice showed that deficiency in neutrophil activity and chromatin decondensation impairs the development of gallstones, while the bile composition was not affected. Importantly, pharmacological targeting of neutrophil activity or NET formation by small molecules blocked gallstone formation and growth.
This study provides profound evidence that gallstone development can be reduced through pharmacological interference with neutrophils and the corresponding NET formation. The findings pave the way for promising therapeutic approaches to prevent gallstone formation and growth.
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Muñoz LE, Boeltz S, Bilyy R, Schauer C, Mahajan A, Widulin N, Krenn V, Biermann M, Podolska MJ, Hahn J, Knopf J, Maueröder C, Paryzhak S, Dumych T, Zhao Y, Neurath MF, Hoffmann MH, Fuchs TA, Leppkes M, Schett G, Herrmann M: Neutrophil Extracellular Traps Initiate Gallstone Formation. (2019) Immunity | https://doi.org/10.1016/j.immuni.2019.07.002