Sticky DNA Traps Cause Gallstone Formation
Sticky DNA traps produced by immune cells enable gallstones to stick together and grow, new research has revealed.
Gallstones are stones that form in the gall bladder when the fats and minerals found in bile harden into a crystalline structure. Gallstones can cause inflammation and infections, depending on their size.
Researchers investigated gallstones in patients due to have surgery to remove them. On the surface of the gallstones they observed signs of neutrophil extracellular traps (NETs). NETs are sticky webs of DNA that immune cells produce when they are under attack from foreign cells, used to clump the cells together and make them easier to destroy.
However, when the immune cells target NETs towards cholesterol and calcium crystals in the gall bladder, the sticky DNA acts as an adhesive to allow lots of small crystals to clump together and form a gallstone. To confirm this, researchers mixed existing gallstones with neutrophils. The gallstones quickly joined together to form even larger gallstones.
Genetic treatments were used to try and disrupt the function of NET formation and prevent the formation of gallstones in mice. Researchers produced mice with a point mutation in the Ncf1 gene, which prevents a cell’s ability to undergo oxidative burst, essential for NET formation. They also engineered mice to lack the PADI4 gene, which enables chromatin condensation, also needed for NET formation.
Both genetically engineered mice groups and controls were fed a diet to induce gallstone formation. The mice with engineered genetic changes to prevent NET formation showed fewer gallstones with smaller sizes.
The anti-Ly6G antibody was used to deplete neutrophils in mice with gallstones. The mice with depleted neutrophils had both fewer and smaller gallstones than the control group. This demonstrates that both drug-based and genetic based treatments show promise for developing preventative treatments for gallstones.