Dynamics of liver injury and regeneration in a mouse model of bacterial infection related acute-on-chronic liver injury (BI-ACLI)

Background and aim Acute-on-chronic liver failure (ACLF) is defined as acute decompensation of chronic liver disease in the presence of an acute trigger like bacterial infection (BI). We aimed to establish a mouse model, mimicking BI-ACLF conditions to study physiological processes during disease onset and progression.

Methods C57BL/6J (n=16; wild-type, WT) and Abcb4-/- (n=16; knock-out, KO) mice were intraperitoneally injected either with 0.9% NaCl or 4 mg/kg LPS to establish four groups: control (WT+NaCl), acute (WT+LPS), chronic (KO+NaCl) and acute-on-chronic group (KO+LPS). RNA sequencing was used to identify differentially expressed genes (DEGs). DEGs were confirmed by qRT-PCR and immunoblot.

Results IFN-γ (stimulation of M1-polarization) and CD64, CD86 and CCR7 (M1 markers) were upregulated in the KO-LPS group only. M2 markers remained unchanged (CD206 and Arg1) or downregulated (CD163). IL-17 and IL-22 are known to be regulated differentially in response to IL-6 and TGF-β levels, i.e., IL-6 alone induces T cells (TH17 cells) to produce IL-22, whereas the combination of both IL-6 and TGF-β results in the production of IL-17 but not IL-22. In line with this tissue response to liver injury, we observed high-levels of IL-6 and IL-22 in KO-LPS group, but IL-17 and TGF-β did not differ.

Conclusions M1/M2 imbalance in our model implies active disease progression, since M2 macrophages are involved in resolution of inflammation and regeneration. On the other hand, high levels of IL-22, which promotes tissue protection and regeneration, suggest an ongoing protective tissue response. Further research is required to delineate these dynamic pathophysiological processes.

Publikationsverlauf

Artikel online veröffentlicht:
18. Januar 2023