Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4+CD25+Foxp3+Tregs through IDO-Kyn-AHR axis

Wang, Fengge; Li, Meng; Ma, Ding; Cai, Zecheng; Liu, Lei; Wang, Juncheng; Zhang, Wenjie; Zhao, Lin; Zhai, Chengfeng; Xu, Yuekang

doi:10.1016/j.intimp.2023.109758

Cited by 21 publications

(15 citation statements)

References 49 publications

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“…DC cells could sense in ammation-related signals and choose to maintain peripheral T cells in a quiescent state in the absence of in ammation (27)(28). It has been proven that experimentally DC-expressed IDO reduces atherosclerotic lesions by inducing aortic CD4CD25Foxp3Treg expansion through IDO-Kyn-AHR axis, suggesting a negative correlation between DCs and aortic in ammatory diseases (29). It is consistent with our immune in ltration results between TAAD and healthy group.…”

Section: Discussionsupporting

confidence: 91%

Identification of Hub Immune-Related Genes and Immune Infiltration in Type A Aortic Dissection by Bioinformatics Analysis

Leng

Luo

et al. 2023

Preprint

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Background: Type A Aortic Dissection (TAAD), a devastating cardiovascular emergency with high incidence, is associated with immune inflammation. Intervention targets and regulatory mechanism of TAAD remain unclear and necessitate further research. Three datasets (GSE153434, GSE52093, GSE190635) of TAAD were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were explored, and immune-related genes, WGCNA and DEGs (IRWDEGs) were overlapped. Four hub genes were screened from 132 IRWDEGs by Protein-Protein Interaction (PPI) Network and least absolute shrinkage selection operator (LASSO) constructed by GSE52093 and validated by GSE190635 and GSE153434 merged datasets . The hub genes were further validated by the GSE52093 dataset and in TAAD tissues by using polymerase chain reaction(PCR) . Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene set enrichment analysis (GSEA) were constructed to explore potential related signaling pathways. Immune cell infiltration in TAAD was analyzed by ssGSEA, and their association with the four hub genes were explored. Results: A total of 132 IRWDEGs were overlapped, twelve key modules were screened, and finally 4 hub genes including CCL2, CXCL8, ENG, and TEK were identified. The expression of CCL2, CXCL8 and ENG was predicted to increase, whereas TEK was predicted to decrease. These results were verified in another independent dataset and human TAAD tissues. The hub genes were related to immune infiltration, indicated by type 17 T helper cell, activated dendritic cell, and active B cell. Conclusion: The effect of CCL2, CXCL8, ENG and TEK in immune infiltration were identified.

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Section: Discussionsupporting

confidence: 91%

Identification of Hub Immune-Related Genes and Immune Infiltration in Type A Aortic Dissection by Bioinformatics Analysis

Leng

Luo

et al. 2023

Preprint

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“… 107 For example, the transplant of dendritic cells overexpressing IDO into pro-atherosclerotic mice was associated with a reduction in vascular inflammation and aortic lesions. 108 This was accompanied by increased KYN levels and AhR expression, and the effects on lesions were negated by the application of an AhR antagonist. 108 This highlights the positive feedback loop of this pathway in which AhR induces IDO but IDO/KP activation also promotes AhR expression which reinforces the discovery that several IDO inhibitors are unexpectedly also AhR ligands, and therefore may paradoxically increase IDO expression.…”

Section: Kynurenine Pathwaymentioning

confidence: 99%

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

Summers,

Thomas Broome,

Pang

et al. 2024

Int J�Tryptophan�Res

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Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body’s ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.

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“…In addition, Tregs directly interact with ILC2s, secrete IL-10 and TGF-β to expand ILC2 population and promote IL-13 secretion [26] . Indoleamine 2,3-dioxygenase controls the kynurenine pathway, regulates T-cell-mediated inflammatory response, and induces tolerance [27] . DCs overexpressing indoleamine 2,3-dioxygenase can promote Tregs expansion and protect against AS by increasing kynurenine levels in the aorta [27] .…”

Section: General Biological Functions Of Tregs In Cvdsmentioning

confidence: 99%

Regulatory T cells and cardiovascular diseases

Hu,

Li,

Cheng

2023

Chinese Medical Journal

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Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases (CVDs). Regulatory T cells (Tregs) are typical immune regulatory cells with recognized immunosuppressive properties. Despite the immunosuppressive properties, researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration. Previous studies unveiled the heterogeneity of Tregs in the heart and aorta, which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function. This review briefly summarizes the functional principles of Tregs, also including the synergistic effect of Tregs and other immune cells in CVDs. We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis, hypertension, abdominal arterial aneurysm, pulmonary arterial hypertension, Kawasaki disease, myocarditis, myocardial infarction, and heart failure. Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair, maintaining the stability of the local microenvironment. Given that the specific mechanism of Tregs functioning in CVDs remains unclear, we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.

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Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4+CD25+Foxp3+Tregs through IDO-Kyn-AHR axis

Cited by 21 publications

References 49 publications

Identification of Hub Immune-Related Genes and Immune Infiltration in Type A Aortic Dissection by Bioinformatics Analysis

Identification of Hub Immune-Related Genes and Immune Infiltration in Type A Aortic Dissection by Bioinformatics Analysis

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

Regulatory T cells and cardiovascular diseases

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