2. Academic Validation
  3. BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury

BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury

  • Cell Death Dis. 2023 Nov 15;14(11):743. doi: 10.1038/s41419-023-06268-z.
Wen Zhang # 1 2 3,  Kai Liu # 1,  Guang-Ming Ren 1 4,  Yu Wang 1 5,  Ting Wang 4 6,  Xian Liu 1 7,  Dong-Xu Li 1 2,  Yang Xiao 1,  Xu Chen 1 4,  Ya-Ting Li 4 6,  Yi-Qun Zhan 1 4,  Shen-Si Xiang 1 4,  Hui Chen 1 4,  Hui-Ying Gao 1 4,  Ke Zhao 1 4,  Miao Yu 1 4,  Chang-Hui Ge 4,  Chang-Yan Li 1 4,  Zhi-Qiang Ge 2,  Xiao-Ming Yang 8 9 10,  Rong-Hua Yin 11 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
  • 2 Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
  • 3 Tianjin Key Laboratory of Food Science and Biotechnology, School of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China.
  • 4 Beijing Institute of Radiation Medicine, Beijing, 100850, China.
  • 5 School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China.
  • 6 College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, 100124, China.
  • 7 Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.
  • 8 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. [email protected].
  • 9 Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China. [email protected].
  • 10 Beijing Institute of Radiation Medicine, Beijing, 100850, China. [email protected].
  • 11 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. [email protected].
  • 12 Beijing Institute of Radiation Medicine, Beijing, 100850, China. [email protected].
  • # Contributed equally.
PMID: 37968261 DOI: 10.1038/s41419-023-06268-z
Abstract

BRISC (BRCC3 isopeptidase complex) is a deubiquitinating Enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1β, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.

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