[en] The liver immune microenvironment is a key element in the development of hepatic inflammation in NAFLD. ApoA4 deficiency increases the hepatic lipid burden, insulin resistance, and metabolic inflammation. However, the effect of ApoA4 on liver immune cells and the precise immune cell subsets that exacerbate fatty liver remain elusive. The aim of this study was to profile the hepatic immune cells affected by ApoA4 in NAFL. We performed scRNA-seq on liver immune cells from WT and ApoA4-deficient mice administered a high-fat diet. Immunostaining and qRT-PCR analysis were used to validate the results of scRNA-seq. We identified 10 discrete immune cell populations comprising macrophages, DCs, granulocytes, B, T and NK&NKT cells and characterized their subsets, gene expression profiles, and functional modules. ApoA4 deficiency led to significant increases in the abundance of specific subsets, including inflammatory macrophages (2-Mφ-Cxcl9 and 4-Mφ-Cxcl2) and activated granulocytes (0-Gran-Wfdc17). Moreover, ApoA4 deficiency resulted in higher Lgals3, Ctss, Fcgr2b, Spp1, Cxcl2, and Elane levels and lower Nr4a1 levels in hepatic immune cells. These genes were consistent with human NAFLD-associated marker genes linked to disease severity. The expression of NE and IL-1β in granulocytes and macrophages as key ApoA4 targets were validate in the presence or absence of ApoA4 by immunostaining. The scRNA-seq data analyses revealed reprogramming of liver immune cells resulted from ApoA4 deficiency. We uncovered that the emergence of ApoA4-associated immune subsets (namely Cxcl9+ macrophage, Cxcl2+ macrophage and Wfdc17+ granulocyte), pathways, and NAFLD-related marker genes may promote the development of NAFL. These findings may provide novel therapeutic targets for NAFL and the foundations for further studying the effects of ApoA4 on immune cells in various diseases.
Disciplines :
Immunology & infectious disease
Author, co-author :
Liu, Xiao-Huan; National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Zhou, Jin-Ting; Key laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
Yan, Chun-Xia; College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, China ; Department of Pathology, Bio-Evidence Sciences Academy, The Western China Science and Technology Innovation Port, Xi'an Jiaotong University, Xi'an, China
Cheng, Cheng; Key laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
Fan, Jing-Na; Key laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
Xu, Jing; Division of Endocrinology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Zheng, Qiangsun; Division of Cardiology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Bai, Qiang ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF)
Li, Zongfang; National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Li, Shengbin; Key laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
Li, Xiaoming; National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
Language :
English
Title :
Single-cell RNA sequencing reveals a novel inhibitory effect of ApoA4 on NAFL mediated by liver-specific subsets of myeloid cells.
NSCF - National Natural Science Foundation of China [CN] Natural Science Foundation of Shaanxi Province
Funding text :
This work was supported by grants from the National Natural Science Foundation of China (No. 81770798) and Natural Science Foundation of Shaanxi Province (No.2020JM-405).
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