Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-β1 signaling pathway

Abstract

Splenectomy has been reported to improve liver fibrosis in patients with cirrhosis and hypersplenism. However, the mechanisms remain unclear. Tumor necrosis factor superfamily 14 (TNFSF14; also known as LIGHT) is highly expressed in the context of fibrosis and promotes disease progression in patients with fibrotic diseases such as pulmonary and skin fibrosis. Here, we determined whether splenectomy controls the production of LIGHT to improve liver fibrosis. Splenectomy reduced serum LIGHT levels in cirrhotic patients with hypersplenism and a ConA-induced liver fibrosis mouse model. Blocking LIGHT resulted in the downregulation of TGF-β1 in RAW264.7 cells. LIGHT treatment of RAW264.7 and JS1 cells in coculture regulated transforming growth factor-β1 (TGF-β1) expression through the activation of JNK signaling. Small interfering RNA-mediated silencing of lymphotoxin β receptor (LTβR) in macrophages resulted in pronounced decreases in the levels of fibrosis and αSMA in JS1 cells. These results indicated that LIGHT bound to LTβR and drove liver fibrosis in vitro. Blocking TGF-β1 abolished the effect of LIGHT in vitro. Furthermore, the administration of recombinant murine LIGHT protein-induced liver fibrosis with splenectomy, while blocking LIGHT without splenectomy improved liver fibrosis in vivo, revealing that the decrease in fibrosis following splenectomy was directly related to reduced levels of LIGHT. Thus, high levels of LIGHT derived from the spleen and hepatic macrophages activate JNK signaling and lead to increased TGF-β1 production in hepatic macrophages. Splenectomy attenuates liver fibrosis by decreasing the expression of LIGHT.

AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway

“…The PI3K/AKT signaling pathway plays an important regulatory role in the progression of liver fibrosis [ 37 ]. In addition, activation of the ERK and JNK pathways is significantly positively correlated with activation of hepatic stellate cells, which exacerbates liver fibrosis [ [37] , [38] , [39] , [40] ]. AKAP12 knockout in hepatocytes activated PI3K-AKT pathway while had little or no effect on the JNK and ERK pathways.…”

Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB

“…TNFSF14, which acts downstream of RelB, promotes hepatic stellate cell activation and exacerbates liver fibrosis ( 38 ). Staining with Masson 3 and Sirius Red confirmed that TP decreased collagen deposition around the portal fields in BDL mice ( Figures 5A,B ).…”

“…In addition to its presence in cholangiocytes, RelB is expressed in Kupffer cells ( 55 ) and hepatocytes ( 36 ). RelB-regulated TNFSF14 is presumed to promote hepatic stellate cell activation and the resulting liver fibrosis ( 38 ). Our assays of serum TNFSF14 levels indicated that TP reduced the BDL-induced increase in the TNFSF14 level; this may partly explain why TP relieves hepatic inflammation and fibrosis.…”

A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients

“…Tumor necrosis factor superfamily 14 (TNFSF14) was the main driver of the former network with a markedly strong interaction between subclusters HEP2 and HEP5. This interaction could represent an underlying homeostatic mechanism between distinct hepatocytes responsible for regulating TGF- β 1 expression in liver fibrosis 60 . Interestingly, TGF β-centric communication was observed between MES8 and HEP7 cells (a COVID-19-specific subset), suggesting stressed hepatocytes could be driving fibrogenic HSC activation.…”