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.