RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions
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PROVIDER: PRJNA422980 | ENA |
REPOSITORIES: ENA
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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
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.
2012-10-24 | GSE35340 | GEO
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
Project description:Langerhans-cell histiocytosis (LCH) is characterized by heterogeneous lesions containing CD207+ Langerhans cells (LCs) and lymphocytes. In this study, we isolated CD207+ cells and CD3+ T cells from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Based on these results, we propose a new model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes.
2010-03-15 | GSE16395 | GEO
Project description:This study aims to identify the cell of origin of Langerhans Cell Histiocytosis and the molecular mechanisms of its pathogenesis.
2018-07-29 | GSE114181 | GEO
Project description:Langerhans-cell histiocytosis (LCH) is characterized by heterogeneous lesions containing CD207+ Langerhans cells (LCs) and lymphocytes. In this study, we isolated CD207+ cells and CD3+ T cells from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Based on these results, we propose a new model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes. Cell-specific gene expression from LCH biopsy specimens was evaluated by comparing hybridization signal from amplified cDNA on Affymetrix gene chips (U133A Plus 2.0) (Table1). Three sets of comparisons were performed: 1) Thirteen LCH CD207+ samples were compared to 12 control skin LCH CD207+ samples. 2) Seven LCH lesion CD3+ samples were compared to 7 peripheral blood CD3+ samples from the same patients. 3) Twelve LCH lesion CD3+ samples were compared to 4 pooled control tonsil CD3+ samples (5 individual tonsil CD3+ samples/pool).
2010-03-23 | E-GEOD-16395 | biostudies-arrayexpress
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
Project description: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.
| S-EPMC5748846 | biostudies-literature
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
Project description:Senescent Langerhans cell histiocytosis cells arise from both dendritic cell (DC) and monocyte/DC3 lineages
| PRJNA727557 | ENA