Abstract
Fulminant hepatic failure (FHF) is a clinical syndrome characterized by a sudden and severe impairment in liver function. However, the precise mechanism of immune dysregulation that is significant to FHF pathogenesis remains unclear. Enhancer of zeste homolog 2 (EZH2) has been implicated in inflammation as a regulator of immune cell function. In this study, we investigated the role of EZH2 in an animal model of human FHF induced by Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS). We demonstrated that EZH2 depletion in dendritic cells (DCs) and pharmacological inhibition of EZH2 using GSK126 both significantly ameliorated liver injury and improved the survival rates of mice with P. acnes plus LPS-induced FHF, which could be attributed to the decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells and induction of regulatory T cells. The expression of EZH2 in DCs was increased after P. acnes administration, and EZH2 deficiency in DCs suppressed DC maturation and prevented DCs from efficiently stimulating CD4+ T-cell proliferation. Further mechanistic analyses indicated that EZH2 deficiency directly increased the expression of the transcription factor RUNX1 and thereby suppressed the immune functions of DCs. The functional dependence of EZH2 on RUNX1 was further illustrated in DC-specific Ezh2-deficient mice. Taken together, our findings establish that EZH2 exhibits anti-inflammatory effects through inhibition of RUNX1 to regulate DC functions and that inhibition of EZH2 alleviates P. acnes plus LPS-induced FHF, probably by inhibiting DC-induced adaptive immune responses. These results highlight the effect of EZH2 on DCs, serving as a guide for the development of a promising immunotherapeutic strategy for FHF.
Highlights
Fulminant hepatic failure (FHF), known as acute liver failure, is characterized by a sudden and severe impairment of liver function, which develops secondary to infection, toxin exposure, or immune-mediated attack and is a rare but potentially fatal disease[1,2,3]
We demonstrated that Enhancer of zeste homolog 2 (EZH2) depletion in dendritic cells (DCs) and pharmacological inhibition of EZH2 using GSK126 both significantly ameliorated liver injury and improved the survival rates of mice with P. acnes plus LPS-induced FHF, which could be attributed to the decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells and induction of regulatory T cells
The results showed that both the protein and mRNA expression levels of EZH2 were increased in FHF Dendritic cells (DCs) compared to control DCs (Supplementary Figs. 1A, 2A, and Fig. 1D–F)
Summary
Fulminant hepatic failure (FHF), known as acute liver failure, is characterized by a sudden and severe impairment of liver function, which develops secondary to infection, toxin exposure, or immune-mediated attack and is a rare but potentially fatal disease[1,2,3]. Mice injected with heat-killed Propionibacterium acnes (P. acnes) followed by lipopolysaccharide (LPS) are one of the most commonly used animal models of fulminant hepatitis[4,5,6,7] This model can be classified into two different phases: the priming phase, in which the injection of P. acnes generates granulomas, and the elicitation phase, in which LPS activates granuloma-forming cells, leading. Dendritic cells (DCs), as antigenrepresenting cells, play a key role in the initiation of immune responses[8] They have been suggested to play an active role in the development of liver failure, and the distribution and number of DCs reflect the progression of liver failure[9]. In the priming phase of P. acnes plus LPS-induced FHF, DCs and T cells cluster in the liver, leading to further proliferation and polarization of CD4+ T cells.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
