PhD Scientific Days 2022

Pharmaceutical Sciences II. (Poster discussion will take place in the Aula during the Coffee Break)

Interleukin-1ß blockade improves cardiac diastolic function, but does not ameliorate key features of NASH in an aged mouse model

Text of the abstract

Introduction: Non-alcoholic steatohepatitis (NASH) is a chronic, age-related inflammatory disease of the liver. IL- 1ß is a key mediator of systemic inflammation-driven aging (aka. inflamm-aging), deteriorating cardiovascular and metabolic functions. Therefore, blocking IL-1ß and related signaling is a potential therapeutic target in these pathologies.
Aims: We aimed to investigate the hepatic and cardiac effects of anti-IL-1ß monoclonal antibody treatment in an aged mouse model of NASH.
Method: Aged male C57Bl/6J mice were fed with control (CON) diet or choline deficient (CDAA) diet and were treated with isotype control or anti-IL-1ß mAb for 8 weeks. Cardiac functions were assessed by echocardiography and subsequent strain analysis. Liver samples were analyzed by immunohistochemistry and qRT-PCR.
Results: Echocardiography revealed improved cardiac diastolic function in anti-IL-1ß treated aged mice with NASH. Histological and gene expression analyses showed marked hepatic fibrosis in CDAA fed group, but IL-1ß inhibition only affected fibrosis beneficially on the molecular level. Hepatic inflammatory changes were not affected beneficially by IL-1 blockade. Immunohistochemistry and qRT-PCR analyses of PCNA showed marked hepatocyte proliferation in CDAA fed animals, that was not influenced by IL-1β neutralization. IL-1ß inhibition led to increased hepatic expression of Pd-1 and Ctla4, while in the CDAA fed aged group, we found increased expression of Pd-l1.
Conclusion: IL-1ß inhibition improved cardiac diastolic function; however, it did not ameliorate inflammation and fibrosis in NASH, and even promoted expression of hepatic immune-checkpoints, potentially giving rise to malignant transformation, along with the NASH related hepatocellular proliferation.
Funding:
European Union’s Horizon 2020 Research and Innovation Programme no. 739593.
Momentum Research Grant LP-2021-14.
National Heart Program NVKP_16-1-2016-0017.
Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology in Hungary TKP/ITM/NKFIH.
National Research, Development and Innovation Office of Hungary OTKA-FK-134751.
New National Excellence Program of the Ministry of Human Capacities ÚNKP-21-3-II.
Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése EFOP-3.6.3.-VEKOP-16-2017-00009