PhD Scientific Days 2023

Budapest, 22-23 June 2023

Pharmaceutical Sciences - Posters E

IL‑1β inhibition prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH

Dániel Kucsera 1,2,3, Viktória E. Tóth 1,2,3, Nabil V. Sayour 1,2,3, Tamás Kovács 1,2,3,
Tamás G. Gergely 1,2,3, Mihály Ruppert 4, Tamás Radovits 4, Alexandra Fábián 4, Attila Kovács 4,
Béla Merkely 4, Péter Ferdinandy 1,5 & Zoltán V. Varga 1,2,3

1 Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
2 HCEMM‑SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.
3 MTA‑SE Momentum Cardio‑Oncology and Cardioimmunology Research Group, Semmelweis University, Budapest, Hungary.
4 Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
5 Pharmahungary Group, Szeged, Hungary.

Text of the abstract

Introduction: Interleukin-1β (IL-1β) is a key mediator in the pathophysiology of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of inflamm-aging. IL-1β contributes to cardio-metabolic decline, and may even have crucial effect on hepatic oncogenic transformation. Therefore, IL-1β is a potential therapeutic target in these pathologies.
Aims: We aimed to investigate the hepatic and cardiac effects of anti-IL-1β monoclonal antibody treatment in an aged animal model of NASH.
Methods: 24 months old male C57Bl/6J mice were fed with control or choline deficient (CDAA) diet and were treated with isotype control or anti-IL-1β Mab for 8 weeks. Cardiac functions were assessed by conventional—and 2D speckle tracking echocardiography. Liver samples were analyzed by immunohistochemistry and qRT-PCR.
Results: Echocardiography revealed improved cardiac diastolic function in anti-IL-1β treated mice with NASH. Marked hepatic fibrosis developed in CDAA-fed group, but IL-1β inhibition affected fibrosis only at transcriptomic level. Hepatic inflammation was not affected by the IL-1β inhibitor. PCNA staining revealed intensive hepatocyte proliferation in CDAA-fed animals, which was not influenced by neutralization of IL-1β. IL-1β inhibition increased hepatic expression of Pd-1 and Ctla4, while Pd-l1 expression increased in NASH.
Conclusion: IL-1β inhibition improved cardiac diastolic function, but did not ameliorate features of NASH; moreover, even promoted hepatic immune checkpoint expression, with concomitant NASH-related hepatocellular proliferation.
Funding: The work was supported by the European Union’s Horizon 2020 No. 739593, Momentum Research Grant, TKP/ITM/NKFIH, OTKA-FK-134751, ÚNKP-21-3-II, EFOP-3.6.3.-VEKOP-16-2017-00009, ‘Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése.