Details zur Publikation
|DOI / URL||Link|
|Titel (primär)||Bidirectional role of NLRP3 during acute and chronic cholestatic liver injury|
|Autor||Frissen, M.; Liao, L.; Schneider, K.M.; Djudjaj, S.; Haybaeck, J.; Wree, A.; Rolle-Kampczyk, U.; von Bergen, M.; Latz, E.; Boor, P.; Trautwein, C.;|
|Journal / Serie||Hepatology|
|POF III (gesamt)||F11;|
|Keywords||Inflammasome; Primary Biliary Cholangitis; Cholestasis; Bile duct ligation; Fibrosis|
Cholestatic liver injury leads to cell death and subsequent inflammation and fibrosis. As shown for primary biliary cholangitis (PBC) the mechanisms and circuits between different cell death pathways leading to disease progression are incompletely defined. Ligation of the common bile duct (BDL) is a well‐established murine model to mimic cholestatic liver injury. Here, we hypothesised that pyroptotic cell death by the Nlrp3 inflammasome plays an essential role during human and murine cholestasis.
Material & Methods
NLRP3 activation was analysed in humans with cholestatic liver injury. WT and Nlrp3‐/‐ mice were subjected to BDL for 2 or 28 days.
Chronic cholestasis in humans and mice is associated with NLRP3 activation and correlates with disease activity. Acute BDL in Nlrp3‐deficient mice triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death. In contrast, NLRP3 deletion led to decreased liver injury and inflammation in chronic cholestasis. Moreover, bridging fibrosis was observed in WT, but not in NLRP3 knockout mice 28 days after BDL In contrast, lack of NLRP3 expression attenuated kidney injury and fibrosis after acute and chronic BDL. Importantly, MCC950 administration ‐ a NLRP3 small molecule inhibitor ‐ reduced BDL‐induced disease progression in WT mice.
NLRP3 activation correlates with disease activity in PBC patients. NLRP3 has a differential role during acute and chronic cholestatic liver injury in contrast to kidney injury. Disease progression during chronic cholestasis can be targeted via small molecules and thus suggests a potential clinical benefit for humans, attenuating liver and kidney injury.
|Frissen, M., Liao, L., Schneider, K.M., Djudjaj, S., Haybaeck, J., Wree, A., Rolle-Kampczyk, U., von Bergen, M., Latz, E., Boor, P., Trautwein, C. (2020):
Bidirectional role of NLRP3 during acute and chronic cholestatic liver injury