Neutrophil extracellular traps form the nidus of human gall stones

• Applicant: Dr. Christine Schauer, Ph.D.
• Subject Area: Rheumatology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324113754

With a prevalence of 10 to 15% in adult Europeans and US-Americans, gallstones are the most common digestive disease requiring the admission to hospital. However, the exact molecular conditions and mechanisms of human gall stone formations are still elusive. Neutrophils are the most abundant leukocytes in humans. They are essential for the innate immune response against invading pathogens and attack microorganisms amongst other mechanisms by the formation of neutrophil extracellular traps (NETs). The latter are webs of extracellular chromatin fibers decorated with serine proteases that trap and kill microbes. In our preliminary work we observed that NETs can frequently be found in human and murine gall stones. The depletion of neutrophils and the inhibition of NETosis in mice reduced the formation of murine gall stones. We, therefore, hypothesize that stone formation is driven by neutrophil invasion and subsequent release of NETs that form the nidus for the growing gall stone.The current application will further test this concept and comprises three different aims: Aim 1: To test whether NETs are constituents of gall stones and of stones at other anatomical sites of the bodyAim 2: To address whether NETosis is the crucial step in initiating and/or acceleration of stone formation in vivoAim 3: To model NETosis-mediated gall stone development in vitro and to investigate the role of bacteria as a further trigger in this process.

• DFG Programme: Research Grants