Exosomal miR-146a-5p Derived from HSCs Accelerates Sepsis-induced Liver Injury by Suppressing KLF-4

Abstract Background This study aims to investigate whether and how LPS-activated hepatic stellate cells (HSCs) could regulate macrophage activity, as well as to explore the impact of microRNA(miRNA) in exosomes from HSCs in this process. Methods Mice subjected to lipopolysaccharide (LPS) or Cecal Ligation and Puncture (CLP) were used to explore sepsis-induced liver injury. Liver injury was evaluated by HE staining, and AST and ALT levels were measured. LPS-Exo or N-LPS-Exo from HSCs were added to hepatic macrophages, and the expression of iNOS, IL-1β, and TNF-α was detected by Western Blotting. miRNA microarray analysis and PCR were used to evaluate differentially expressed miRNAs between LPS-Exo and N-LPS-Exo. Target genes were screened using the TargetScan database and verified by luciferase assays and WB. Inflammation and macrophage activity were observed in vivo by HE and CD86 staining in mice injected with PKH67-labeled LPS-Exo or N-LPS-Exo. Results Sepsis-related liver injury activates hepatic stellate cells, which regulate macrophage activity through exosomes. Specifically, exosomal miR-146a-5p secreted by hepatic stellate cells targets KLF-4, regulating the macrophage inflammatory response via the JNK signaling pathway. Conclusion Exosomes containing miRNA-146a-5p released from HSCs following LPS treatment may increase macrophage sensitivity to LPS and trigger an inflammatory response. Exosomal miR-146a-5p derived from HSCs accelerates sepsis-induced liver injury by suppressing KLF-4 expression.