TY  - JOUR
A1  - Torres Núñez, Sandra
A1  - Brol, Maximilian
A1  - Magdaleno, Fernando
A1  - Schierwagen, Robert
A1  - Uschner, Frank Erhard
A1  - Klein, Sabine
A1  - Ortiz, Cristina
A1  - Tyc, Olaf
A1  - Bachtler, Nadine
A1  - Stunden, James
A1  - Bertheloot, Damien
A1  - Kitanovic, Ana
A1  - Sanchez, Brian
A1  - Schrum, Jacob
A1  - Roush, William R.
A1  - Franchi, Luigi
A1  - Byth, Kate
A1  - Latz, Eicke
A1  - Trebicka, Jonel
T1  - The sspecific NLRP3 antagonist IFM-514 decreases fibrosis and inflammation in experimental murine non-alcoholic steatohepatitis
T2  - Frontiers in Molecular Biosciences
N2  - Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached. Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.
KW  - inflammasome
KW  - liver fibrosis
KW  - steatosis
KW  - NASH
KW  - caspase-1
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62435
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-624358
SN  - 2296-889X
N1  - This study received funding from the Deutsche Forschungsgemeinschaft (SFB TRR57 and CRC1382), European Union's Horizon 2020 Research and Innovation Programme (Galaxy, No. 668031, MICROB-PREDICT, No. 825694, and DECISION No. 84794), Societal Challenges-Health, Demographic Change, and Well-Being (No. 731875), Cellex Foundation (PREDICT), LIVERHOPE (No. 731875), Enable (funded by Hessian Ministry of Higher Education, Research, Science and the Arts) and deep-HCC (German Federal Ministry of Education and Research). These funders had no involvement in the design of the study.
VL  - 8
IS  - art. 715765
SP  - 1
EP  - 15
PB  - Frontiers
CY  - Lausanne
ER  -