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

Rui Shi; Jiangang Wang; Zhen Zhang; Yiping Leng; Alex F Chen

doi:10.1016/j.lfs.2022.121339

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

Life Sci. 2023 Feb 15:315:121339. doi: 10.1016/j.lfs.2022.121339. Epub 2023 Jan 5.

Authors

Rui Shi¹, Jiangang Wang², Zhen Zhang³, Yiping Leng⁴, Alex F Chen⁵

Affiliations

¹ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China; Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University, Changsha, China.
² Health Management Center, the Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: 600410@csu.edu.cn.
³ Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University, Changsha, China.
⁴ The Affiliated Changsha Central Hospital, Research Center for Phase I Clinical Trials, Hengyang Medical School, University of South China, Changsha, Hunan, China.
⁵ Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University, Changsha, China; Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, China. Electronic address: chenfengyuan@xinhuamed.com.cn.

PMID: 36621538
DOI: 10.1016/j.lfs.2022.121339

Abstract

Aims: Liver 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 methods: ASGR1-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 findings: ASGR1 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 Ly6C^hi inflammatory monocytes in PBMCs, and restrained CD45⁺CD11b^hiF4/80⁺Ly6C^lo 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.

Significance: ASGR1 is a negative regulator for sepsis-induced liver injury and survival.

Keywords: ASGR1; Immune-inflammation; Liver injury; Monocyte derived macrophage; Sepsis.

MeSH terms

Activating Transcription Factors / metabolism
Animals
Cell Differentiation
Chemical and Drug Induced Liver Injury, Chronic* / metabolism
Leukocytes, Mononuclear / metabolism
Macrophages / metabolism
Mice
Mice, Inbred C57BL
Monocytes / metabolism
NF-kappa B / metabolism
Sepsis* / complications
Sepsis* / metabolism

Substances

NF-kappa B
Atf5 protein, mouse
Activating Transcription Factors