PMID- 33717169
OWN - NLM
STAT- MEDLINE
DCOM- 20210916
LR  - 20230715
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Immunological Feature and Transcriptional Signaling of Ly6C Monocyte Subsets From 
      Transcriptome Analysis in Control and Hyperhomocysteinemic Mice.
PG  - 632333
LID - 10.3389/fimmu.2021.632333 [doi]
LID - 632333
AB  - BACKGROUND: Murine monocytes (MC) are classified into Ly6C(high) and Ly6C(low) 
      MC. Ly6C(high) 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. METHODS: RNA-seq 
      was performed in blood Ly6C(high) and Ly6C(low) MC sorted by flow cytometry from 
      control and HHcy cystathionine beta-synthase gene-deficient (Cbs(-/-)) mice. 
      Transcriptome data were analyzed by comparing Ly6C(high) vs. Ly6C(low) in control 
      mice, Ly6C(high) vs. Ly6C(low) in Cbs(-/-) mice, Cbs(-/-) Ly6C(high) vs. control 
      Ly6C(high) MC and Cbs(-/-) Ly6C(low) vs. control Ly6C(low) 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. RESULTS: A total of 7,928 
      SDE genes and 46 canonical pathways derived from it were identified. Ly6C(high) 
      MC exhibited activated neutrophil degranulation, lysosome, cytokine 
      production/receptor interaction and myeloid cell activation pathways, and 
      Ly6C(low) 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. Ly6C(high) 
      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. Ly6C(high) MC 
      expressed higher levels of macrophage (MPhi) markers, whereas, Ly6C(low) MC highly 
      expressed lymphocyte markers in both mice. HHcy in Cbs(-/-) mice reinforced 
      inflammatory features in Ly6C(high) MC by upregulating inflammatory TFs (Ets1 and 
      Tbx21) and strengthened lymphocytes functional adaptation in Ly6C(low) MC by 
      increased expression of CD3, DR3, ICOS, and Fos. Finally, we established 3 groups 
      of transcriptional models to describe Ly6C(high) to Ly6C(low) MC subset 
      differentiation, immune checkpoint regulation, Ly6C(high) MC to MPhi subset 
      differentiation and Ly6C(low) MC to lymphocyte functional adaptation. 
      CONCLUSIONS: Ly6C(high) MC displayed enriched inflammatory pathways and favored 
      to be differentiated into MPhi. Ly6C(low) MC manifested activated T-cell signaling 
      pathways and potentially can adapt the function of lymphocytes. HHcy reinforced 
      inflammatory feature in Ly6C(high) MC and strengthened lymphocytes functional 
      adaptation in Ly6C(low) MC.
CI  - Copyright (c) 2021 Yang, Liu, Sun, Fang, Snyder, Saredy, Ji, Shen, Qin, Wu, Yang 
      and Wang.
FAU - Yang, Pingping
AU  - Yang P
AD  - Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang 
      University, Nanchang, China.
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
FAU - Liu, Lu
AU  - Liu L
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
FAU - Sun, Lizhe
AU  - Sun L
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
AD  - Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an 
      Jiaotong University, Xi'an, China.
FAU - Fang, Pu
AU  - Fang P
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
FAU - Snyder, Nathaniel
AU  - Snyder N
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
FAU - Saredy, Jason
AU  - Saredy J
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
FAU - Ji, Yong
AU  - Ji Y
AD  - Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing 
      Medical University, Nanjing, China.
FAU - Shen, Wen
AU  - Shen W
AD  - Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Qin, Xuebin
AU  - Qin X
AD  - Tulane National Primate Research Center, School of Medicine, Tulane University, 
      Covington, LA, United States.
FAU - Wu, Qinghua
AU  - Wu Q
AD  - Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Yang, Xiaofeng
AU  - Yang X
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
FAU - Wang, Hong
AU  - Wang H
AD  - Department of Pharmacology, Center for Metabolic Disease Research, Lewis Kats 
      School of Medicine, Temple University, Philadelphia, PA, United States.
LA  - eng
GR  - R01 HL138749/HL/NHLBI NIH HHS/United States
GR  - P51 OD011104/OD/NIH HHS/United States
GR  - R01 HL130233/HL/NHLBI NIH HHS/United States
GR  - R01 HL131460/HL/NHLBI NIH HHS/United States
GR  - R01 HL082774/HL/NHLBI NIH HHS/United States
GR  - R01 DK104116/DK/NIDDK NIH HHS/United States
GR  - R01 HL147565/HL/NHLBI NIH HHS/United States
GR  - R01 DK113775/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210225
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Antigens, Ly)
RN  - 0 (Immune Checkpoint Proteins)
RN  - 0 (Ly-6C antigen, mouse)
RN  - 0 (Transcription Factors)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Antigens, Ly/*immunology/metabolism
MH  - Cell Differentiation/immunology
MH  - Cystathionine beta-Synthase/deficiency
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - Hyperhomocysteinemia/*immunology/metabolism
MH  - Immune Checkpoint Proteins/genetics
MH  - Inflammation
MH  - Lymphocytes/immunology
MH  - Lysosomes/immunology
MH  - Macrophages/immunology
MH  - Mice
MH  - Monocytes/*immunology/metabolism
MH  - Signal Transduction
MH  - Transcription Factors/genetics
PMC - PMC7947624
OTO - NOTNLM
OT  - hyperhomocysteinemia
OT  - immune checkpoint
OT  - immunological gene
OT  - locus C (Ly6C) monocyte subset
OT  - lymphocyte antigen 6 complex
OT  - transcription factor
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/03/16 06:00
MHDA- 2021/09/18 06:00
PMCR- 2021/01/01
CRDT- 2021/03/15 06:58
PHST- 2020/11/23 00:00 [received]
PHST- 2021/01/11 00:00 [accepted]
PHST- 2021/03/15 06:58 [entrez]
PHST- 2021/03/16 06:00 [pubmed]
PHST- 2021/09/18 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.632333 [doi]
PST - epublish
SO  - Front Immunol. 2021 Feb 25;12:632333. doi: 10.3389/fimmu.2021.632333. eCollection 
      2021.