Dataset Information

Adaptive Immune Response Signaling Is Suppressed in Ly6C^high Monocyte but Upregulated in Monocyte Subsets of ApoE ^-/- Mice - Functional Implication in Atherosclerosis.

ABSTRACT:

Rationale

Inflammatory monocyte (MC) subset differentiation is a major feature in tissue inflammatory and atherosclerosis. The underlying molecular mechanism remains unclear.

Objective

This study aims to explore molecule targets and signaling which determinate immunological features in MC subsets.

Methods and results

Blood Ly6C^high and Ly6C^low MC subsets from control and ApoE ^-/- mice were isolated by flow cytometry sorting and subjected for bulk high-throughput RNA-sequencing. Intensive bioinformatic studies were performed by analyzing transcriptome through four pairs of comparisons: A) Ly6C^high vs Ly6C^low in control mice; B) Ly6C^high vs Ly6C^low in ApoE^-/- mice; C) ApoE^-/- Ly6C^high vs control Ly6C^high MC; D) ApoE^-/- Ly6C^low vs control Ly6C^low MC. A total of 80 canonical pathways and 16 enriched pathways were recognized by top-down analysis using IPA and GSEA software, and further used for overlapping analysis. Immunological features and signaling were assessed on four selected functional groups, including MHCII, immune checkpoint, cytokine, and transcription factor (TF). Among the total 14578 significantly differentially expressed (SDE) genes identified though above four comparison, 1051 TF and 348 immunological genes were discovered. SDE immunological genes were matched with corresponding upstream SDE TF by IPA upstream analysis. Fourteen potential transcriptional axes were recognized to modulate immunological features in the Ly6C MC subset. Based on an intensive literature search, we found that the identified SDE immune checkpoint genes in Ly6C^high MC are associated with pro-inflammatory/atherogenic balance function. Immune checkpoint genes GITR, CTLA4, and CD96 were upregulated in Ly6C^low MC from all mice and presented anti-inflammatory/atherogenic features. Six cytokine genes, including Ccl2, Tnfsf14, Il1rn, Cxcl10, Ccl9, and Cxcl2, were upregulated in Ly6C^high MC from all mice and associated with pro-inflammatory/atherogenic feature. Cytokine receptor gene Il12rb2, Il1r1, Il27ra, Il5ra, Ngfr, Ccr7, and Cxcr5 were upregulated in Ly6C^low MC from all mice and presented anti-inflammatory/atherogenic features. MHCII genes (H2-Oa, H2-DMb2, H2-Ob, H2-Eb2, H2-Eb1, H2-Aa, and Cd74) were elevated in Ly6C^low MC from all mice. ApoE ^-/- augmented pro-atherogenic/inflammatory and antigen-presenting cells (APC) feature in both subsets due to elevated expression of cytokine genes (Cxcl11, Cntf, Il24, Xcl, Ccr5, Mpl, and Acvr2a) and MHCII gene (H2-Aa and H2-Ea-ps). Finally, we modeled immunological gene expression changes and functional implications in MC differentiation and adaptive immune response for MC subsets from control and ApoE^-/- mice.

Conclusions

Ly6C^high MC presented pro-inflammatory/atherogenic features and lower APC potential. Ly6C^low MC displayed anti-inflammatory/atherogenic features and higher APC potential. ApoE ^-/- confers upon both subsets with augmented pro-atherogenic/inflammatory function and APC potential.

SUBMITTER: Yang P

PROVIDER: S-EPMC8721109 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectiveThe incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by the gut after food intake leading to pancreatic insulin secretion and glucose lowering. Beyond its role in glucose control, GLP-1 was found in mice and men to beneficially modulate the process of atherosclerosis, which has been linked to improved cardiovascular outcome of patients with diabetes at high cardiovascular risk treated with GLP-1 receptor agonists. However, little is known on the role of the other main incretin in the cardiovascular system. The aim of this study was to characterize GIP in atherosclerotic cardiovascular disease.Methods and resultsSerum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD (peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1-42) in ApoE-/- mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of Nf?B, JNK-, ERK, and p38 in endotoxin activated macrophages.ConclusionElevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.

Project description: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.

Dataset Information

Adaptive Immune Response Signaling Is Suppressed in Ly6C^high Monocyte but Upregulated in Monocyte Subsets of ApoE ^-/- Mice - Functional Implication in Atherosclerosis.

Rationale

Objective

Methods and results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Adaptive Immune Response Signaling Is Suppressed in Ly6Chigh Monocyte but Upregulated in Monocyte Subsets of ApoE -/- Mice - Functional Implication in Atherosclerosis.

Rationale

Objective

Methods and results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Adaptive Immune Response Signaling Is Suppressed in Ly6C^high Monocyte but Upregulated in Monocyte Subsets of ApoE ^-/- Mice - Functional Implication in Atherosclerosis.