Transcriptional enhancement of GBP-5 by BATF aggravates sepsis-associated liver injury via NLRP3 inflammasome activation

FASEB J. 2021 Jun;35(6):e21672. doi: 10.1096/fj.202100234R.

Abstract

Strong inflammatory response triggered by the activation of the innate immune system is one typical characteristic of sepsis-associated liver injury (SALI). Guanylate-binding protein 5 (GBP-5) is a component of cell-autonomous immunity and known to be associated with inflammation. Currently, whether GBP-5 participates in SALI and its roles in this disease are yet to be investigated. Using a lipopolysaccharide (LPS)-induced SALI mouse model, we found GBP-5 was highly expressed in LPS-treated mice, and its expression was tightly related to the serum concentrations of live injury markers and inflammatory cytokines, liver damage scores by H&E staining, and amounts of apoptotic hepatocytes by TUNEL staining. Moreover, GBP-5 overexpression was found to aggravate LPS-induced SALI by promoting the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome, then facilitated the production of pro-inflammatory cytokines, eventually induced hepatocyte cell death. Direct transcriptional activation of GBP-5 by basic leucine zipper ATF-like transcription factor (BATF) was identified and further validated. This study unveils a transcriptional upregulation of GBP-5 by interacting with BATF, which promotes the progression of LPS-induced SALI through NLRP3 inflammasome activation, and provides novel therapeutic insights for halting the progression of liver injury in various liver diseases.

Keywords: BATF; GBP-5; NLRP3 inflammasome; acute liver injury; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • GTP-Binding Proteins / genetics*
  • Inflammasomes / immunology*
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Liver Diseases / etiology
  • Liver Diseases / metabolism
  • Liver Diseases / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Sepsis / complications*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • GTP-Binding Proteins
  • Gbp5 protein, mouse