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

Interleukin-1 beta (IL-1 beta) is a key mediator of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of systemic inflammation-driven aging. IL-1 beta contributes to cardio-metabolic decline, and may promote hepatic oncogenic transformation. Therefore, IL-1 beta is a potential therapeutic target in these pathologies. We aimed to investigate the hepatic and cardiac effects of an IL-1 beta targeting monoclonal antibody in an aged mouse model of NASH. 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-1 beta Mab for 8 weeks. Cardiac functions were assessed by conventional-and 2D speckle tracking echocardiography. Liver samples were analyzed by immunohistochemistry and qRT-PCR. Echocardiography revealed improved cardiac diastolic function in anti-IL-1 beta treated mice with NASH. Marked hepatic fibrosis developed in CDAA-fed group, but IL-1 beta inhibition affected fibrosis only at transcriptomic level. Hepatic inflammation was not affected by the IL-1 beta inhibitor. PCNA staining revealed intensive hepatocyte proliferation in CDAA-fed animals, which was not influenced by neutralization of IL-1 beta. IL-1 beta inhibition increased hepatic expression of Pd-1 and Ctla4, while Pd-l1 expression increased in NASH. In conclusion, IL-1 beta 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.

Automated summary

This study aimed to investigate the hepatic and cardiac effects of an IL-1 beta targeting monoclonal antibody in an aged mouse model of NASH. The results showed that IL-1 beta inhibition improved cardiac diastolic function, but did not ameliorate features of NASH and may promote hepatic oncogenic transformation.