Immunological Feature and Transcriptional Signaling of Ly6C Monocyte Subsets From Transcriptome Analysis in Control and Hyperhomocysteinemic Mice

Frontiers in Immunology

Lizhe Sun¹  Wen Shen²  Qinghua Wu²  Lu Liu³  Pu Fang³  Pingping Yang³  Xiaofeng Yang³  Nathaniel Snyder³  Jason Saredy³  Hong Wang³  Yong Ji⁴  Xuebin Qin⁵ 

[1] Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China;Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China;Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States;Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China;Tulane National Primate Research Center, School of Medicine, Tulane University, Covington, LA, United States;

关键词: lymphocyte antigen 6 complex;    locus C (Ly6C) monocyte subset;    hyperhomocysteinemia;    transcription factor;    immunological gene;    immune checkpoint;   

DOI  :  10.3389/fimmu.2021.632333

来源: DOAJ

【 摘 要 】

BackgroundMurine monocytes (MC) are classified into Ly6Chigh and Ly6Clow MC. Ly6Chigh MC is the pro-inflammatory subset and the counterpart of human CD14++CD16+ intermediate MC which contributes to systemic and tissue inflammation in various metabolic disorders, including hyperhomocysteinemia (HHcy). This study aims to explore molecule signaling mediating MC subset differentiation in HHcy and control mice.MethodsRNA-seq was performed in blood Ly6Chigh and Ly6Clow MC sorted by flow cytometry from control and HHcy cystathionine β-synthase gene-deficient (Cbs-/-) mice. Transcriptome data were analyzed by comparing Ly6Chigh vs. Ly6Clow in control mice, Ly6Chigh vs. Ly6Clow in Cbs-/- mice, Cbs-/- Ly6Chigh vs. control Ly6Chigh MC and Cbs-/- Ly6Clow vs. control Ly6Clow MC by using intensive bioinformatic strategies. Significantly differentially expressed (SDE) immunological genes and transcription factor (TF) were selected for functional pathways and transcriptional signaling identification.ResultsA total of 7,928 SDE genes and 46 canonical pathways derived from it were identified. Ly6Chigh MC exhibited activated neutrophil degranulation, lysosome, cytokine production/receptor interaction and myeloid cell activation pathways, and Ly6Clow MC presented features of lymphocyte immunity pathways in both mice. Twenty-four potential transcriptional regulatory pathways were identified based on SDE TFs matched with their corresponding SDE immunological genes. Ly6Chigh MC presented downregulated co-stimulatory receptors (CD2, GITR, and TIM1) which direct immune cell proliferation, and upregulated co-stimulatory ligands (LIGHT and SEMA4A) which trigger antigen priming and differentiation. Ly6Chigh MC expressed higher levels of macrophage (MΦ) markers, whereas, Ly6Clow MC highly expressed lymphocyte markers in both mice. HHcy in Cbs-/- mice reinforced inflammatory features in Ly6Chigh MC by upregulating inflammatory TFs (Ets1 and Tbx21) and strengthened lymphocytes functional adaptation in Ly6Clow MC by increased expression of CD3, DR3, ICOS, and Fos. Finally, we established 3 groups of transcriptional models to describe Ly6Chigh to Ly6Clow MC subset differentiation, immune checkpoint regulation, Ly6Chigh MC to MΦ subset differentiation and Ly6Clow MC to lymphocyte functional adaptation.ConclusionsLy6Chigh MC displayed enriched inflammatory pathways and favored to be differentiated into MΦ. Ly6Clow MC manifested activated T-cell signaling pathways and potentially can adapt the function of lymphocytes. HHcy reinforced inflammatory feature in Ly6Chigh MC and strengthened lymphocytes functional adaptation in Ly6Clow MC.

【 授权许可】

Unknown