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

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

  • Exp Mol Med. 2021 Mar;53(3):393-406. doi: 10.1038/s12276-021-00574-2.
Qing-Shan Liang  # 1,  Jian-Gang Xie  # 2,  ChaoPing Yu 2,  ZhuSheng Feng 2,  JingChang Ma 3,  Yuan Zhang 4 5,  Dong Wang 1,  JianGuo Lu 6,  Ran Zhuang 7 8,  Jikai Yin 9
Affiliations

Affiliations

  • 1 Department of General Surgery, The Second Affiliated Hospital of Air Force Military Medical University, 710038, Xi'an, Shaanxi, China.
  • 2 Department of Emergency, The First Affiliated Hospital of Air Force Military Medical University, 710032, Xi'an, Shaanxi, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Air Force Military Medical University, 710032, Xi'an, Shaanxi, China.
  • 4 Transplant Immunology Laboratory, School of Basic Medical Sciences, Air Force Military Medical University, 710032, Xi'an, Shaanxi, China.
  • 5 Institute of Medical Research, Northwest Polytechnic University, 710072, Xi'an, Shaanxi, China.
  • 6 Department of General Surgery, The Second Affiliated Hospital of Air Force Military Medical University, 710038, Xi'an, Shaanxi, China. lujguo@fmmu.edu.cn.
  • 7 Department of Immunology, School of Basic Medical Sciences, Air Force Military Medical University, 710032, Xi'an, Shaanxi, China. fmmuzhr@fmmu.edu.cn.
  • 8 Transplant Immunology Laboratory, School of Basic Medical Sciences, Air Force Military Medical University, 710032, Xi'an, Shaanxi, China. fmmuzhr@fmmu.edu.cn.
  • 9 Department of General Surgery, The Second Affiliated Hospital of Air Force Military Medical University, 710038, Xi'an, Shaanxi, China. Tdyjk07@fmmu.edu.cn.
  • # Contributed equally.
PMID: 33654222 DOI: 10.1038/s12276-021-00574-2
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.

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