Xcr1+ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression
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PROVIDER: PRJNA1172307 | ENA |
REPOSITORIES: ENA
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Project description:Atherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1+ cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in atherosclerosis development remains highly controversial. We first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established Xcr1Cre-Gfp Rosa26LSL-DTA Apoe–/– mice, a novel and complex genetic model, in which cDC1 was constitutively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4+ and CD8+ subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1+ cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1+ cDC1 cells via Xcl1 by establishing Xcl1–/–Apoe–/– mice. Xcl1–/–Apoe–/– mice exhibited decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation, indicating that Xcl1 contributes to cDC1-mediated atherosclerotic lesion development. Our results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.
2025-09-08 | GSE279370 | GEO
Project description:XCR1 is known as a signature receptor of type 1 conventional dendritic cells To compare the transcriptomic differences of WT and XCR1 deficient type 1 conventional dendritic cells, we conducted microarry using type 1 conventional dendritic cells from WT and XCR1 KO mice
2024-05-20 | GSE267410 | GEO
Project description:We sought to compare the overall transcriptomic differences between TLR stimulated WT and XCR1-deficient type 1 conventional DCs. In addition, we also wanted to investigate functional role of XCR1 signaling in WT type 1 conventional DCs by treating recombinant murine XCL1, a ligand of XCR1 to these cells as well
2023-06-01 | GSE228392 | GEO
Project description:Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as non-lymphoid tissues. Steady state XCR1+ cDC1 display a pre-activated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1.
2023-07-31 | GSE237715 | GEO
Project description:Dendritic cells (DC) play critical roles in central and peripheral T cell tolerance. DC found in the steady-state periphery undergo an homeostatic, tolerogenic, maturation that promotes interaction with naive T cells and induction of abortive responses. In contrast, thymic DC are thought to exist solely in an immature state. In this study, we show that XCR1+ thymic DC constitutively mature into a stage characterized by high levels of molecules involved in T cell activation. This unanticipated mature stage corresponded to a third of the XCR1+ thymic DC and fully accounted for their ability to cross-present self-antigens to developing T cells. Transcriptomic analysis of the XCR1+ DC found in thymus and steady-state periphery revealed that their maturation involves profound and convergent changes. Unexpectedly, maturation resulted in down-regulation of genes conferring their specific function on XCR1+ DC. Paradoxically, upon maturation, central and peripheral tolerogenic XCR1+ DC up-regulated many genes thought to drive pro-inflammatory T-cell responses. Thus, our results reveal that thymic XCR1+ DC undergo constitutive maturation and emphasize the common mechanisms operating for both central and peripheral tolerance induction by XCR1+ DC. DC were isolated from lymphoid organs as previously described (Vremec et al., 2000). DC subsets were sorted by flow cytometry according to the marker combinations described in the âcharacteristics: phenotypeâ field for each sample.
2016-08-22 | E-GEOD-71166 | biostudies-arrayexpress
Project description:Dendritic cells (DC) play critical roles in central and peripheral T cell tolerance. DC found in the steady-state periphery undergo an homeostatic, tolerogenic, maturation that promotes interaction with naive T cells and induction of abortive responses. In contrast, thymic DC are thought to exist solely in an immature state. In this study, we show that XCR1+ thymic DC constitutively mature into a stage characterized by high levels of molecules involved in T cell activation. This unanticipated mature stage corresponded to a third of the XCR1+ thymic DC and fully accounted for their ability to cross-present self-antigens to developing T cells. Transcriptomic analysis of the XCR1+ DC found in thymus and steady-state periphery revealed that their maturation involves profound and convergent changes. Unexpectedly, maturation resulted in down-regulation of genes conferring their specific function on XCR1+ DC. Paradoxically, upon maturation, central and peripheral tolerogenic XCR1+ DC up-regulated many genes thought to drive pro-inflammatory T-cell responses. Thus, our results reveal that thymic XCR1+ DC undergo constitutive maturation and emphasize the common mechanisms operating for both central and peripheral tolerance induction by XCR1+ DC.
2016-08-22 | GSE71166 | GEO
Project description:XCR1+ type 1 conventional dendritic cells drive liver pathology in Non-Alcoholic Steatohepatitis.
| PRJNA716614 | ENA
Project description:Comparative analysis of WT and XCR1 KO type 1 conventional dendritic cells [array]
| PRJNA1111449 | ENA
Project description:Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions, which underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDC), and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NALFD/NASH spectrum showed that cDC type 1 (cDC1) were more abundant and activated in disease. Genomic analysis of cDC-T pairs in liver draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1 blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH, and identifies XCR1+ cDC1 as an important driver of liver pathology.
2021-05-21 | GSE169445 | GEO
Project description:XCR1+ type 1 conventional dendritic cells drive liver pathology in Non-Alcoholic Steatohepatitis [scRNA-seq]
| PRJNA716618 | ENA