Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

ABSTRACT: Neurodegenerative diseases (ND) are characterized by a progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent dendritic cells that drive formation of lesions. Some patients with systemic LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by hematopoietic cells that are clonal with systemic LCH lesion histiocytes. Strikingly, we discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enabling migration of into the brain where they differentiate into senescent, inflammatory macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs synergistically reduced parenchymal infiltration, neuroinflammation and neurologic damage in preclinical LCH-ND. MAPK activation in circulating myeloid cells represents a novel and targetable mechanism of ND.

ORGANISM(S): Mus musculus

PROVIDER: GSE227984 | GEO | 2024/03/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dissecting the Transcriptomic Landscape of Circulating Mononuclear Phagocytes in Langerhans Cell Histiocytosis at Single-cell Level

Project description:Langerhans cell histiocytosis (LCH) is a rarely clonal disorder caused by aberrant activation of MAPK pathway, which predominantly affects the mononuclear myeloid lineages. Many efforts have been devoted to tracking precursor cells in circulating blood and bone marrow by detection of BRAFV600E alleles and to exploring the differentiation potential of LCH-related myeloid cells in vitro. However, their cellular and molecular alterations remain unclear. Here, we constructed a single-cell transcriptional landscape of more than 3,000 monocytes and DCs from treatment-naïve pediatric LCH and targeted-therapy pediatric LCH cohorts, unraveling patient to patient heterogeneity and underlying molecular mechanisms of BRAF inhibitor, respectively. In parallel, we further investigated the precise relationship between circulating potential precursors and pathological LCH clusters based on unbiased joint analysis. In addition, we found that the proportion of pDC in Lin-HLA-DR+ population is closely linked with the severity of the disease, providing a novel promising indicator to optimize the stratification strategy. Taken together, our data update the molecular understanding of LCH biology, which might contribute to improvement of clinical therapeutics and promotion of the personalized medicine.

2021-09-15 | GSE151713 | GEO

Notch is active in Langerhans Cell Histiocytosis and confers pathognomonic features on dendritic cells.

Project description:Langerhans cell histiocytosis (LCH) is a disease characterized by the accumulation of eponymous CD1a+ Langerin+ Langerhans-cell (LC)-like dendritic cells (DC) of largely unknown origin. Here we have performed comparative transcriptome analysis of highly purified CD207+/CD1a+ Langerhans cell histiocytosis (LCH) cells derived from different locations and disease courses and three major human dendritic cell lineages: epidermal Langerhans cells, myeloid dendritic cells (mDC1) and plasmacytoid dendritic cells (pDC) in order to investigate the relationship between LCH cells and naturally occurring dendritic cells. Data obtained indicate that LCH cells form a distinct DC entity. Furthermore, we have identified transcripts that are uniquely expressed by LCH cells in comparison to LC, mDC1, and pDC, and induce LCH-specific features in human DC. Primary cells were isolated from peripheral blood (mDC1 and pDC), skin (epidermal Langerhans cells) and CD207+/CD1a+ Langerhans cell histiocytosis (LCH) cells derived from different locations. RNA was isolated from these cells ex vivo.

2012-10-24 | E-GEOD-35340 | biostudies-arrayexpress

Circulating CD1c+ myeloid dendritic cells are precursors to Langerhans cell histiocytosis (LCH) lesion CD1a+CD207+cells

Project description:Expression data from LCH lesion subpopulations and healthy donors' peripheral blood specimens Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder that is characterized by the inflammatory lesions with pathogenic CD1a+CD207+ dendritic cells (DCs). BRAFV600E and other somatic activating MAPK gene mutations have been identified in differentiating bone marrow and blood myeloid cells, but the origin of the LCH lesion CD1a+CD207+DCs and mechanisms of lesion formation remain incompletely defined. In order to identify candidate LCH CD1a+CD207+DCs’ precursor populations, gene expression profiles of LCH lesion CD1a+CD207+DCs were first compared to established gene signatures from human myeloid cell subpopulations. Interestingly, the CD1c+ myeloid DC (mDC) gene signature was most enriched in the LCH CD1a+CD207+DC’ transcriptome. Additionally, the BRAFV600E allele was not only localized to CD1a+CD207-DCs and CD1a+CD207+DCs, but it was also identified in CD1c+mDCs in LCH lesions. Transcriptomes of CD1a+CD207-DCs were nearly indistinguishable from CD1a+CD207+DCs (both CD207low and CD207high subpopulations). Transcription profiles of LCH lesion CD1a+CD207+DCs and peripheral blood CD1c+mDCs from healthy donors were compared to identify potential LCH DC-specific biomarkers. HLADQB2 expression was significantly increased in LCH lesion CD1a+CD207+DCs compared to circulating CD1c+mDCs from healthy donors, and HLA-DQB2 antigen was identified on LCH lesion CD1a+CD207- and CD1a+CD207+DCs as well as on CD1c+(CD1a+CD207-) mDCs, but not in any other lesion myeloid subpopulations. Interestingly, HLADQB2 expression was specific to peripheral blood of patients with BRAFV600E+ peripheral blood mononuclear cells (PBMC), and HLA-DQB2+CD1c+blood cells were highly enriched for the BRAFV600E in these patients. These data support a model where blood CD1c+mDCs with activated ERK migrate to lesion sites where they differentiate into pathogenic CD1a+CD207+ DCs.

2020-01-21 | GSE122476 | GEO

Circulating CD1c+ myeloid dendritic cells are precursors to Langerhans cell histiocytosis (LCH) lesion CD1a+CD207+cells

2020-01-21 | GSE122674 | GEO

Vemurafenib acts as molecular switch in Langerhans Cell Histiocytosis

Project description:Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1a+CD207+ cells. It is most commonly driven by a somatic activating mutation in the BRAF kinase (BRAFV600E). Multisystem disease with risk-organ involvement requires intensive chemotherapy, making BRAF-inhibitors an attractive option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib with salvage chemotherapy who achieved complete clinical and molecular remission. We conclusively show that there is no relationship between blood-BRAF levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of high-risk LCH such as cytopenia, fever, and hypoproteinemia. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping for the BRAFV600E mutation shows its presence in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analysis of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH. Together, our data suggest that while the CD1a+CD207+ histiocytes are the hallmark of LCH, other BRAF-mutated cells themselves contribute significantly to morbidity in patients with multisystem LCH.

2021-09-23 | GSE175480 | GEO

RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions

Project description:Expression data from dendritic cell subsets derived or sorted from control littermate and CD11c-Cre/BRAFV600E(flox-CA) mice Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.

2017-12-20 | GSE108251 | GEO

Notch is active in Langerhans Cell Histiocytosis and confers pathognomonic features on dendritic cells.

2012-10-24 | GSE35340 | GEO

BRAF-V600E utilizes post-transcriptional mechanisms to amplify LPS-induced TNF production in dendritic cells of Langerhans Cell Histiocytosis

Project description:Langerhans Cell Histiocytosis (LCH) is an inflammatory disease characterized by abnormal dendritic cells (DCs) with hyperactive ERK signaling, called “LCH cells”. Since DCs rely on ERK signaling to produce inflammatory signaling molecules in response to pathogenic cues, we hypothesized that hyperactive ERK will enhance DC inflammatory responses. We utilized the BRAF-V600E fl/+: CD11c-Cre mouse model of LCH which hyperactivates MAPK/ERK signaling in DCs. We cultured bone-marrow derived dendritic cells (BMDCs) from LCH and control mice (BRAF-V600E fl/+: Cre0) and stimulated them with LPS with or without a specific BRAF-V600E inhibitor. Polysome Profiling revealed a large and irreversible increase in levels of polysome bound RNA in the LCH-BMDCs compared to WT. We defined the LCH translatome by analyzing total and polysome-bound RNA from BMDCs using the Anota2seq program, which revealed a BRAF-V600E-mediated selective increase in LPS-induced inflammatory proteins.

2022-05-01 | GSE193610 | GEO

Epigenomics and Single-cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis [ATAC-seq]

Project description:Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a characteristic hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mecha-nisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investi-gated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA se-quencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of pro-liferative LCH cells in all analysed biopsies using immunohistochemistry, and we defined the epigenomic and gene-regulatory basis of the different LCH cell subsets using chromatin profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, reflecting complex developmental hierarchies in LCH lesions.

2019-07-30 | GSE133785 | GEO

Epigenomics and Single-cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis [scRNA-seq]

Project description:Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a characteristic hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analysed biopsies using immunohistochemistry, and we defined the epigenomic and gene-regulatory basis of the different LCH cell subsets using chromatin profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, reflecting complex developmental hierarchies in LCH lesions.

2019-07-30 | GSE133704 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data