Abstract
Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.
Highlights
When the liver is challenged with a myriad of pathological stimuli, hepatocytes undergo cell death invariably paralleling a compensatory response that aims at containing the damage, regenerating the liver parenchyma, and restoring hepatic normalcy
To investigate the role of Brahmarelated gene 1 (BRG1) in the pathogenesis of Fulminant hepatitis (FH), a classic animal model was exploited in which hepatocyte conditional BRG1 knockout (LKO) mice and wild type (WT) littermates were injected with Concanavalin A (ConA) (200 mg/kg) via tail vein (Okamoto et al, 2001). 12 h after the injection, the mice were sacrificed to evaluate liver injury
Because infiltration of T lymphocytes and the ensuing inflammatory storm play a key role in the pathogenesis of ConA induced FH, we evaluated the effect of hepatocyte-specific BRG1 deletion on T cell homing
Summary
When the liver is challenged with a myriad of pathological stimuli, hepatocytes undergo cell death (apoptosis, necrosis, necroptosis, autophagy, pyroptosis, ferroptosis, etc.) invariably paralleling a compensatory response that aims at containing the damage, regenerating the liver parenchyma, and restoring hepatic normalcy. One unique feature regarding ConA-induced FH is that hepatic inflammation in this model is exclusively mediated by recruitment and activation of T lymphocytes (Mizuhara et al, 1994). Depending on the dosing scheme, volcanic inflammatory response can occur in the liver as early as 1 h after ConA injection with massive infiltration of T lymphocytes and concomitant upregulation of T cell specific cytokines (Heymann et al, 2015). Ablation of interferon gamma (IFN-γ, encoded by IFNG), a prototypical T cell cytokine, or its cognate receptor (IFNGR1/R2), or its downstream mediator IRF-1 attenuates ConA-induced hepatitis in mice (Ohta et al, 2000; Hong et al, 2002; Jaruga et al, 2004). The transcriptional regulation of these cytokines in the context of FH is not completely understood
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