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

Abstract

Interleukin-1β (IL-1β) is a key mediator of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of systemic inflammation-driven aging. IL-1β contributes to cardio-metabolic decline, and may promote hepatic oncogenic transformation. Therefore, IL-1β is a potential therapeutic target in these pathologies. We aimed to investigate the hepatic and cardiac effects of an IL-1β 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-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. 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. In 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.

NASH triggers cardiometabolic HFpEF in aging mice

“…Similarly to our previous publication [16], we established that IL-1β is relevant not only for the hepatic pathophysiology of NASH, but it is highly expressed in cardiovascular system as well. This highlights that inflammation could be an important therapeutical target, which is further supported by the CANTOS trial [72].…”

“…NASH is characterized by hepatic steatosis with displaced nuclei, extensive inflammation, and fibrosis [15]. In our previous studies, we already showed that 8 weeks of feeding with CDAA diet effectively induces classical histologic signs of NASH [14,16] (Fig. 1A); nonetheless, we performed histologic and molecular analyses to evidence the development of NASH in the present cohort.…”

Exploring the mechanism of dendrobine in treating metabolic associated fatty liver disease based on network pharmacology and experimental validation

“…The IL-1 family cytokines, especially IL-1β, are key mediators in the progression of MASLD to its more severe form, NASH. IL-1β leads to hepatic triglyceride accumulation (steatosis) and is associated with increased pro-inflammatory cytokine expression in MASLD [ 36 ].…”

MMP1, IL-1β, sTNFR-1, and IL-6 are prognostic factors for patients with unresectable or metastatic renal cell carcinoma treated with immune checkpoint inhibitors

“…The relationship between CTLA4 and IL-1β/sTNFR-1 remains unclear. However, IL-1β secretion is regulated by CTLA4-Ig fusion protein [ 30 ], and the administration of IL-1β inhibitors in a mouse model of hepatitis upregulates the expression of PD-1 and CTLA4 in the liver [ 31 ]. Moreover, TNFR-1 contributes to the termination of immune responses through its ability to induce apoptosis, and the possible involvement of CTLA4 in these apoptotic pathways has also been reported [ 32 ].…”