Neutrophil Extracellular Traps in the pathogenesis of PSC

• Applicant: Professor Dr. Thomas Renné, since 1/2020
• Subject Area: Gastroenterology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278045702

Uncontrolled and excessive inflammation contributes to a plethora of disorders. Neutrophils are the most abundant leukocytes during the acute phase of inflammation. Neutrophils, known as short-lived phagocytes, can respond to infectious and inflammatory stimuli with the release Neutrophil Extracellular Traps (NETs). NETs are lattices of DNA strands that are covered with toxic proteins, which feature antimicrobial, cytotoxic, prothrombotic, and immunoregulatory properties. Here, we study how NETs contribute to the pathogenesis of PSC. In brief, we focus on host DNases that degrade and inactivate NETs to limit collateral damage during inflammatory responses. Our central hypothesis is that acquired and/or genetic defects in host DNases lead to an impaired degradation of NETs in PSC patients. In particular, we speculate that an imbalance between NET formation and NET degradation causes an accumulation of NETs within bile ducts that precipitate PSC. To test our hypothesis, we will analyze biosamples from PSC patients, develop a NET driven murine model of PSC, characterize host DNases in bile fluid biochemically and test their use in experimental therapy. If successful, our study will uncover a detrimental role of NETs in the pathogenesis of PSC that can be therapeutically targeted by DNases.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 306: Primär Sklerosierende Cholangitis
• Co-Investigator: Dr. Christina Weiler-Normann
• Ehemaliger Antragsteller: Dr. Tobias Fuchs, until 1/2020