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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 β-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 (MΦ) 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 MΦ subset differentiation and Ly6C low  MC to lymphocyte functional adaptation.    Conclusions  Ly6C high  MC displayed enriched inflammatory pathways and favored to be differentiated into MΦ. 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.

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