ASGR1 promotes liver injury in sepsis by modulating monocyte-to-macrophage differentiation via NF-κB/ATF5 pathway

Abstract

AimsLiver is a pivotal organ for sepsis-induced injury and approximately 40 % of liver injury results from sepsis. During hepatic injury, monocyte-to-macrophage differentiation is a key event because it results in the regulation of immune response. Asialoglycoprotein receptor 1 (ASGR1) is enriched in classical monocyte of peripheral blood mononuclear cells (PBMCs). We aimed to explore the effect of ASGR1 on monocyte-to-macrophage differentiation and the modulation of sepsis-induced liver injury. Main methodsASGR1-knockdown/overexpression THP-1 cells and mice bone marrow-derived macrophages (BMDMs) induced by PMA and 30 % L929-cell conditioned medium were utilized to test the impact of ASGR1 on monocyte-to-macrophage differentiation and molecular mechanism respectively. Expression of differentiation specific factors were assessed via flow cytometry and real-time quantitative PCR. RNA-sequencing (RNA-seq) analysis revealed the effect of ASGR1 on monocyte-to-macrophage differentiation. Further, differentiation specific factors ATF5 and NF-κB pathways were examined via Western blot. The interaction between ASGR1 and ATF5 was further examined by co-IP. Finally, LPS-induced ASGR1-knockdown mice sepsis was used to investigate the effect of ASGR1 on monocyte-to-macrophage differentiation, liver injury and survival. Key findingsASGR1 promoted monocyte-to-macrophage differentiation via up-regulating CD68, F4/80 and CD86. Additionally, inhibited-ASGR1 decreased ATF5 expression by suppressing phosphorylation of NF-κB and IKBa in vitro and in vivo. ASGR1-knockdown mice suppressed Ly6Chi inflammatory monocytes in PBMCs, and restrained CD45+CD11bhiF4/80+Ly6Clo monocyte-derived macrophages and CD45+CD11b+F4/80+Ly6C+ inflammatory macrophages in livers. It also suppressed the level of IL-1β, IL-6, TNF-α and alleviated liver injury and improved survival after sepsis. SignificanceASGR1 is a negative regulator for sepsis-induced liver injury and survival.