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

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.