Macrophage-specific UBA1 knockout attenuates sepsis-induced liver dysfunction by regulating inflammatory responses...

Macrophages in the liver play an important role in the development of sepsis-associated liver dysfunction (SALD). Ubiquitin-activating enzyme E1 (UBA1) is critically involved in protein degradation and inflammatory diseases. However, whether UBA1 in macrophages participates in the development of SALD remains unknown. Sepsis and acute liver injury mouse models were established by caecal ligation and puncture (CLP) in macrophage-specific UBA1-knockout (UBA1^M-KO) and wild-type (UBA1^M-WT) mice. We found that UBA1 expression in liver tissue and macrophages gradually increased and peaked at 48 h after CLP-induced sepsis. Compared with UBA1^M-WT mice, UBA1^M-KO mice presented an improved survival rate; reduced liver dysfunction, macrophage infiltration, ROS levels, lipid accumulation and hepatocyte apoptosis. In vitro coculture of hepatocytes with macrophages confirmed that UBA1^M-KO macrophages ameliorated LPS-induced inflammatory response and hepatocyte injury. Mechanistically, UBA1 interacted with BMAL1 and increased its ubiquitination and degradation, leading to the reduction of REV-ERBα transcriptional activity and subsequent production of proinflammatory cytokines, which ultimately exacerbated SALD. Interestingly, selective inhibition of UBA1 by PYR-41 effectively attenuated SALD. In summary, these findings indicate that macrophage overexpressing UBA1 contributes to the pathogenesis of SALD possibly through regulating the BMAL1-REV-ERBα axis and that targeting UBA1 may represent a promising therapeutic option for the treatment of SALD.