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GSE23212
Mus musculus
3 Downloadable Samples
Description
We describe a novel subset of CD8+ DCs in lymphoid organs of nave mice characterized by expression of the CX3CR1 chemokine receptor. CX3CR1+CD8+ DCs lack hallmarks of classical CD8+ DCs, including IL12 secretion, the capacity to cross-present antigen and their developmental independence of the transcriptional factor BatF3. Gene expression profiling showed that CX3CR1+CD8+ DCs resemble CD8- cDCs. The microarray analysis further revealed a unique plasmacytoid DC (PDC) gene signature of CX3CR1+ CD8+ DCs. A PDC relationship of the cells is further supported by the fact that they harbor characteristic D-J immunoglobulin gene rearrangements and that development of CX3CR1+CD8+ DCs requires E2-2, the critical transcriptional regulator of PDCs. Thus, CX3CR1+ CD8+ DCs represent a unique DC subset, related to but distinct from PDCs.
Publication Title
CX3CR1+ CD8alpha+ dendritic cells are a steady-state population related to plasmacytoid dendritic cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Mouse lung CD11c+ dendritic cells are composed of 2 major DC subsets, the CD103+CD11b-low/intermediate DC (CD103+ DC) and the CD11b-highCD103- DC (CD11b-high DC). These 2 subsets are functionally distinct. Comparison of their functions showed CD103+ DC
Publication Title
Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 21 Downloadable Samples
Description
Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin receptor (LTR). Circumstantial evidence has linked the SMC LTR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-B pathway, whereas LTR signaling by agonistic anti LTR antibody activated both the classical RelA and alternative RelB NF-B pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-B and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTR-RelB activation component of NF-B signaling was obligatory to generate the LTO phenotype. TNFR1-LTR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy.
Publication Title
Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 5 Downloadable Samples
Description
Cultured mouse aorta endothelial cells (from 8-12 weeks old C57BL/6J mice, passage 2-3) were exposed to phosphate buffered saline (control) or a combination of TNFalpha plus agonistic alpha-LTR antibody for 24 hours as described in Ltzer et al. 2009. Arterioscler. Thromb. Vasc. Biol., in press. Total RNA was extracted and microarrays were prepared.
Publication Title
Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 35 Downloadable Samples
Description
We previously observed that formation of aorta and innominate artery atherosclerotic lesions in the intima of hyperlipidemic apoE-deficient mice but not wild-type mice was accompanied by a marked age-dependent adventitial T cell infiltration. As the mice aged, adventitial T cells formed T/T cell-, T/B cell-, and T/B/dendritic cell aggregates adjacent to atherosclerotic lesions. Some of the adventitial infiltrates formed large clusters of various immune cells including T cells, B cells (centrocytes, follicular mantle cells), dendritic cells, follicular dendritic cells, and plasma cells with preferential formation in the suprarenal portion of the abdominal aorta. These data demonstrated that the immune lineage cell composition of atherosclerotic lesions and adventitia were distinct: The macrophage-foam cell-, T cell-, and SMC-dominated cell composition of atherosclerosis lesions versus the presence of immune cells capable of carrying out antigen-dependent T cell-driven humoral immune responses in the adventitia also indicated that immune reactions carried out in lesions or the adventitia are fundamentaly different. To distinguish between immunity-regulating genes in atherosclerosis lesions versus the adventitia, a combination of microarray profiling and laser capture microdissection was used. Stringent filters revealed 1163 differentially up-regulated probesets in apoE-/- mouse aortae at 78 weeks (w) versus 6 w. A fuzzy c-means cluster algorythm identified 2 clusters that significantly differed in their slope angles between time points: An apparent atherosclerosis cluster consisted of 771 probesets and an apparent adventitia cluster consisted of 392 probesets. Up-regulated genes at 32 w mirrored the influx of monocyte/macrophages into intima lesions whereas genes up-regulated between 32-78 w mirrored adventitial inflammation. To segregate both clusters into separate gene ontology (GO) molecular function groups, we determined statistically significant up-regulation (unpaired Student t-test; p < 0.05) between 6-32 w for the atherosclerosis cluster and between 32-78 w for the adventitia cluster. Among others, GO molecular function terms cytokine activity, cytokine binding, and immunoglobulin binding in the atherosclerosis cluster and cytokine activity, chemokine receptor activity, and antigen binding in the ATLO cluster suggested candidate genes in relation to inflammation triggered by macrophages or adventitia infiltration, respectively. Among other prototype atherosclerosis genes such as Itgax (complement receptor 4), Cd68, Lysz (lysozyme), Vcam1, and Icam1, the atherosclerosis cluster showed markedly overrepresented prototype macrophage/foam cell genes regulating inflammation in cytokine activity (GO: 0005125): Spp1 (osteopontin) and Il6; in cytokine binding (GO: 0019955) Cd74, Il10rb, Ccr2, and Ccr5; and in immunoglobulin binding (GO: 00119865) the proinflammatory galactose-binding lectin Lgals3, as well as genes in scavenger receptor activity and lipid transporter activity. By contrast, the adventitia cluster showed overrepresented genes regulating B cell recruitment, B cell maturation, germinal center formation, and autoimmunity in cytokine activity including Cxcl13, Ccl21, and Ltb, in CXC chemokine receptor activity the secondary lymphoid organ counterreceptor of CXCL13 Blr1 (also known as Cxcr5), Cxcr3, and Cxcr6; and in antigen binding several histocompatibility-2 loci and various markedly expressed immunoglobulin genes. As embryonic lymph node development and tertiary lymphoid organ neogenesis share common features signal intensities of genes specifying the GO molecular function term lymph node development (GO: 0048535) were examined in arrays prepared from wild-type and apoE-/- aortae. These results showed that Id2, Nfkb1, and Ltbr were constitutively expressed at significant levels in aortae of both mouse genotypes whereas other genes including Lta, Ltb, Glycam1, and the two lymphorganogenic genes Cxcl13 and Ccl21 were induced at 78 w in apoE-deficient aortae only. Thus, genes expressed by macrophage-foam cells and genes regulating ATLO neogenesis, embryonic lymph node development, or B cell maturation were constitutively expressed in the arterial wall in both genotypes or emerged in a stepwise fashion at 32 w and 78 w. To verify microarray signal intensity data, separate aortae extracts were examined by quantitative RT-PCR (QRT-PCR) analyses of wild-type and apoE-deficient mice at 32 and 78 w. These data showed that array signal values accurately reflected gene transcripts. Cell lineage analyses of the adventitial infiltrate and kinetic aorta microarray- and QRT-PCR analyses thus provided circumstantial evidence that immune responses in atherosclerosis intima lesions and the adventitia were distinct. To examine this possibility further, we selected areas of the abdominal aorta burdened with advanced lesions and separated lesions and corresponding adventitial infiltrates of 78 w old apoE-deficient mice by laser dissection microscopy. In addition, adventitiae of aorta segments that were not associated with adjacent lesions and adventitiae of wild-type mice were prepared. Consistent with the lack of a major adventitial leukocyte infiltration, wild-type adventitiae showed gene expression levels that were similar to lesion-free adventitiae of apoE-deficient mice indicating that atherosclerotic lesions directly affected adventitial inflammation in a segmental fashion. Stringent filter criteria identified genes that were differentially expressed in adventitiae and atherosclerotic lesions. Statistical analyses of overrepresented genes in GO molecular function or biological process groups were particularly instructive in cytokine activity, cytokine binding, antigen processing and presentation as well as in lymph node development. Thus, adventitiae in aorta segments with associated atherosclerotic lesions in cytokine activity showed overrepresentation of genes known to be associated with tertiary lymphoid organ formation including Cxcl13, Ccl21, and Ltb, whereas atherosclerotic lesions showed overrepresentation of prototype atherosclerosis-associated genes Ssp1 (osteopontin), Bmp4 (bone morphogenic protein 4), and Cxc3cl1 (fractalkine); in cytokine binding adventitiae showed overrepresentation of receptors implicated in B cell immunity and autoimmunity including Brl1 (counterreceptor for CXCL13), Ccr7, Tnfrsf4, and Cxcr3 whereas lesions showed overrepresentation of inflammatory mediator receptors including Tnfrs1b, Tgfbr1, and Il7r; moreover, in antigen processing and presentation, adventitiae showed overrepresentation of several histocompatibility loci; additional adventitial gene expression overrepresentations were observed in lymph node development (Fas, SpiB, Ltb, Flt3) whereas lesions showed expression of prototype macrophage genes including Tlr4, Tgfb1, and Tgfb2. These data provide comprehensive topographical transcriptome information in adventitial tissue adjacent to atherosclerotic lesions versus lesions and are expected to form the basis for future cell lineage expression analyses using single cell detection methodology including ISH.
Publication Title
Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Interleukin-33 (IL-33) is elevated in afflicted tissues of patients with mast cell-dependent chronic allergic diseases. Based on its acute effects on mouse mast cells (MCs), IL-33 is thought to play a role in the pathogenesis of allergic disease through MC activation. However, the manifestations of chronic IL-33 exposure on human MC function, which best reflect the conditions associated with chronic allergic disease, are unknown. We now find that long-term exposure of human and mouse MCs to IL-33 results in a substantial reduction of MC activation in response to antigen. This reduction required >72 h exposure to IL-33 for onset and 1-2 wk for reversion following IL-33 removal. This hypo-responsive phenotype was determined to be a consequence of MyD88-dependent attenuation of signaling processes necessary for MC activation including antigen-mediated calcium mobilization and cytoskeletal reorganization; potentially as a consequence of down-regulation of the expression of PLCg1 and Hck. These findings suggest that IL-33 may play a protective, rather than a causative role in MC activation under chronic conditions and, furthermore, reveal regulated plasticity in the MC activation phenotype. The ability to down-regulate MC activation in this manner may provide alternative approaches for treatment of MC-driven disease.
Publication Title
IL-33 induces a hyporesponsive phenotype in human and mouse mast cells.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
Description
E47 represses Foxp3 transcription, albeit indirectly through the activation of unknown negative regulatory of Foxp3 transcription.
Publication Title
Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
The liver is frequently challenged by surgery-induced metabolic overload, viruses, or toxins, which induce the formation of reactive oxygen species. To determine the effect of oxidative stress on liver regeneration and to identify the underlying signalling pathways, we studied liver repair in mice lacking the Nrf2 transcription factor. In these animals, expression of several cytoprotective enzymes was reduced in hepatocytes, resulting in oxidative stress. As a consequence, tissue damage was aggravated, and liver regeneration after partial hepatectomy was delayed.
Publication Title
Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
Description
Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generated a cell (mECK36) that induced KS-like tumors in mice. mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+ and displayed a KSHV and host transcriptomes reminiscent of KS tumors.
Publication Title
In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 12 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation.
Sample Metadata Fields
Specimen part
View Samples