Upregulation of Il-22 and Rantes in a new mouse model of bacterial infection related acute-on-chronic liver injury (BI-ACLI)

Background and aims:

Bacterial infection (BI) is a common acute trigger leading to acute-on-chronic liver failure (ACLF) in humans. We aim to establish a novel BI-ACLF model by intraperitoneal (IP) lipopolysaccharide (LPS) injections in a knock-out mouse with chronic liver injury (Abcb4 ^-/-) to mimic the disease conditions of ACLF.

Methods:

Fifteen week-old C57BL/6J (N = 16) (wild-type, wt) or Abcb4 ^-/- (N = 16) (knock-out, ko) were treated with IP injections of either LPS (4 mg/kg) or saline solution (0.9% NaCl). Plasma and liver samples were collected 6 hours post injection. Hepatic expression levels (relative to Gapdh) of interleukin-6 (Il-6), C-reactive protein (Crp), tumor necrosis factor-α (Tnf-α), regulated on activation, normal T cell expressed and secreted (Rantes), Toll-like receptor 4 (Tlr4), monocyte chemoattractant protein-1 (Mcp1) and interleukin-22 (Il-22) were evaluated by 2^-ΔΔCt method. Variables were evaluated with paired t-tests, and p < 0.05 was considered as significant.

Results:

LPS challenge resulted in rapid upregulation in hepatic expression of Crp (9-fold) and Tlr4 (10-fold), while leading to a dramatic change in IL6, Mcp1, Tnf-α and Rantes mRNA levels with 230-, 150-, 80- and 64-fold increases in wt mice, respectively. Corresponding effects were also observed in ko mice with no differences in terms of liver specific expression of Il-6, Tnf-α, Tlr4 and Mcp1 compared to wt mice. LPS resulted in a more profound upregulation of Rantes expression in Abcb4 ^-/- mice (126-fold vs. 64-fold increase, p = 0.037), but Mcp1 induction was comparable and Crp increase was moderate (9-fold vs. 4-fold, p = 0.026) in ko mice compared to wt mice. No hepatic Il-22 mRNA was detected in NaCl-administered mice, while LPS profoundly stimulated Il-22 expression in both genotypes with a 7.3-fold increase in ko mice compared to wt.

Conclusions:

High expression levels of hepatic cytokines and chemokines after LPS challenge suggest a novel promising approach to model BI-ACLI in Abcb4 ^-/- mice. While excessive inflammatory responses might be dampened in this dual hit model after acute LPS insult, Il-22 and Rantes could specifically trigger inflammatory cascades with harmful consequences on further disease progression.

This study was supported by BMBF LiSyM (031L0051).