FBXW5 aggravates hepatic ischemia/reperfusion injury via promoting phosphorylation of ASK1 in a TRAF6-dependent manner

Int Immunopharmacol. 2021 Oct:99:107928. doi: 10.1016/j.intimp.2021.107928. Epub 2021 Jul 1.

Abstract

Liver ischemia/reperfusion injury (IRI) is an inevitable pathological process exacerbating the occurrence of rejection in liver transplantation. At present, there is still a lack of sufficient cognition for the mechanism as well as effective clinical strategies. F-box/WD repeat-containing protein 5 (FBXW5), a key modulator of stress signalling, was recently reported to participate in hepatic immunity. However, the role of FBXW5 in liver IRI is still unclear. In the present study, we found expression of FBXW5 was increased in liver IRI both in vivo and in vitro. Inhibition of FBXW5 significantly alleviated both mitogen-activated protein kinase (MAPK) and inhibitor of nuclear factor kappa-B kinase (IKK) pathways, thus resulting in cytokine release, hepatic pathological injury and apoptosis. Over-expression of FBXW5 achieved an opposite effect. Investigations on the mechanism showed that FBXW5 intensified hepatic inflammation by promoting phosphorylation of ASK1, while blockade of TRAF6 could abolish this process. Moreover, reinforce of mTOR amplified the anti-inflammatory efficacy derived from inhibition of FBXW5, indicating the function of FBXW5/ASK1/TRAF6 axis in hepatic IRI might be relatively independent of mTOR-guided M2 polarization of Kupffer cell. Taken together, FBXW5 could be a key accelerator in liver IRI by enhancing activation of ASK1 in a TRAF6-dependent manner. The joint intervention towards both FBXW5 and mTOR might be a promising strategy to protect liver from IRI.

Keywords: ASK1; FBXW5; Inflammation; Liver ischemia/reperfusion injury; TRAF6.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Apoptosis
  • Cytokines / metabolism
  • Enzyme Inhibitors / metabolism
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kupffer Cells
  • Liver
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Animal
  • Phosphorylation
  • Phosphotransferases / antagonists & inhibitors
  • Reperfusion Injury / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Enzyme Inhibitors
  • F-Box Proteins
  • FBXW5 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Tifab protein, human
  • Phosphotransferases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human