Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

Abstract

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68 macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

Identification of Key Genes Related to Immune Infiltration of Cirrhosis via Bioinformatics Analysis

“…Neutrophils are usually recruited to the liver at the early stage of liver injury to clear apoptosis hepatocytes [19] and it releases cell-free DNA with strong pro-in ammatory effect [20] . Cirrhosis mouse model showed the development of liver brosis was alleviated by deletion or ablation of neutrophils of neutrophil chemokines [21,22] . In the brosing process, injection-induced in ammation and then triggered macrophages to gather in the liver, which then induces the activation of hepatic stellate cells (HSCs) by producing cytokines and chemokines [23] .…”

Roseotoxin B alleviates cholestatic liver fibrosis through inhibiting PDGF-B/PDGFR-β pathway in hepatic stellate cells

“…It is well known that pathologic cellular apoptosis is an important nexus of liver injury and fibrosis 22,26 . Generally, the cellular apoptosis is the first pathologic response to liver injury 22,27 . However, the dysregulated apoptosis can disrupt the integrity of hepatocytes and aggravate hepatic inflammation 22,[28][29][30] .…”

A Review of CXCL1 in Cardiac Fibrosis

“…Neutrophils play an important role in liver injury ( 61 ). Cholestatic liver injury is accompanied with infiltration of neutrophils and upregulated expression of CXCL1 ( 62 , 63 ). Decreased level of CXCL1 is observed in treatment of non-alcoholic steatohepatitis and hepatic fibrosis.…”