Roquin-1 resolves sepsis-associated acute liver injury by regulating inflammatory profiles via miRNA cargo in extracellular vesicles
Lei Zheng,
Wei Ling,
Deming Zhu,
Zhi Li,
Yousheng Li,
Haoming Zhou,
Lianbao Kong
Affiliations
Lei Zheng
Hepatobiliary Center/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China; Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao-tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China
Wei Ling
Hepatobiliary Center/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China
Deming Zhu
Hepatobiliary Center/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China
Zhi Li
Hepatobiliary Center/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China
Yousheng Li
Department of General Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao-tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P.R. China; Corresponding author
Haoming Zhou
Hepatobiliary Center/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China; Corresponding author
Lianbao Kong
Hepatobiliary Center/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China; Corresponding author
Summary: Sepsis-associated acute liver injury (SALI) is an independent risk for sepsis-induced death orchestrated by innate and adaptive immune responses. Here, we found that Roquin-1 was decreased during SALI and expressed mainly in monocyte-derived macrophages. Meanwhile, Roquin-1 was correlated with the inflammatory profiles in humans and mice. Mechanically, Roquin-1 in macrophages promoted Ago2-K258-ubiquitination and inhibited Ago2-S387/S828-phosphorylation. Ago2-S387-phosphorylation inhibited Ago2-miRNA’s complex location in multivesicular bodies and sorting in macrophages-derived extracellular vesicles (MDEVs), while Ago2-S828-phosphorylation modulated the binding between Ago2 and miRNAs by special miRNAs-motifs. Then, the anti-inflammatory miRNAs in MDEVs decreased TSC22D2 expression directly, upregulated Tregs-differentiation via TSC22D2-STAT3 signaling, and inhibited M1-macrophage-polarization by TSC22D2-AMPKα-mTOR pathway. Furthermore, WT MDEVs in mice alleviated SALI by increasing Tregs ratio and decreasing M1-macrophage frequency synchronously. Our study showed that Roquin-1 in macrophages increased Tregs-differentiation and decreased M1-macrophage-polarization simultaneously via miRNA in MDEVs, suggesting Roquin-1 can be used as a potential tool for SALI treatment and MDEVs engineering.
