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TY  - THES
AU  - Peltzer, Mona Tatjana
TI  - The role of pyroptosis and inflammasome-mediated inflammation during liver disease progression
PB  - RWTH Aachen University
VL  - Dissertation
CY  - Aachen
M1  - RWTH-2025-10615
SP  - 1 Online-Ressource : Illustrationen
PY  - 2025
N1  - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University 2026
N1  - Dissertation, RWTH Aachen University, 2025
AB  - Chronic liver diseases are characterized by chronic inflammation, cell death and compensatory proliferation and can progress from early fibrosis to cirrhosis and ultimately leading to the development of hepatocellular carcinoma (HCC). Among various risk factors, metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a major contributor. While the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome signaling is known to regulate inflammation through the release of the pro-inflammatory cytokines Interleukin-1β (IL-1β) and Interleukin-18 (IL 18) and pyroptotic cell death via Gasdermin D (GSDMD), its role in hepatocarcinogeneses remains unclear. Hence, the aim of this study was to investigate the role of NLRP3 and the receptors of its downstream cytokines, IL-1β (IL-1R) and IL 18 (IL-18R) in inflammation- and cholangitis associated carcinogenesis. Additionally, the study aimed to determine the contribution of GSDMD mediated pyroptosis to acute liver injury and the progression of MASH. The role of NLRP3, IL-1R and IL-18R was examined in a N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl4) - induced HCC mouse model. Reduced inflammation and tumor burden were found in Nlrp3-/- and Il1r-/ , but not in Il18r-/- mice. The deletion of either Nlrp3 or Il1r showed reduced activation of Kupffer cells and hepatic stellate cells. In addition, the absence of NLRP3 or IL-1R resulted in increased anti-tumor immunity. To explore NLRP3 involvement in cholestasis associated carcinogenesis, multidrug resistance gene 2 knockout (Mdr2 / ) and Mdr2 / /Nlrp3-/- mice were used. Nlrp3 deletion in cholestatic Mdr2 / mice significantly decreased immune cell infiltration, hepatocellular death and tumor development. The role of GSDMD was assessed in Gsdmd / mice. Following CCl4-induced acute liver injury, Gsdmd deletion could significantly reduce liver damage. This was accompanied by reduced infiltration of immune cells and pro-inflammatory cytokine expression. MASH progression was analyzed in wildtype (WT) and Gsdmd / mice fed with a choline-deficient L-amino acid defined diet (CDAA). During MASH progression, the deletion of Gsdmd resulted in less fibrosis, decreased expression of pro-inflammatory cytokines, reduced activation of hepatic stellate cells and altered immune cell infiltration. Altogether, the present study provides novel insights into the pivotal role of NLRP3 signaling in the progression of chronic inflammation during different liver diseases. NLRP3 and IL-1R signaling were shown to contribute to carcinogenesis in inflammation and in cholestasis associated carcinogenesis, while IL-18R appears dispensable. Moreover, GSDMD-mediated pyroptosis was identified as a central mechanism in acute liver injury and MASH associated fibrogenesis.
LB  - PUB:(DE-HGF)11
DO  - DOI:10.18154/RWTH-2025-10615
UR  - https://publications.rwth-aachen.de/record/1023327
ER  -