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Identification of miR-181a target mRNAs by RIP-CHIP during terminal differentiation of DC-SIGN+ mo-DCs

ABSTRACT: DC-SIGN+ monocyte-derived dendritic cells (mo-DCs) play important roles in bacterial infections and inflammatory diseases, but the factors regulating their differentiation and proinflammatory status remain poorly defined. Here, we identify a micro-RNA, miR-181a, and a molecular mechanism that simultaneously regulate the acquisition of DC-SIGN+ expression and the activation state of DC-SIGN+ mo-DCs. Specifically, we show that miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation and limits its sensitivity and responsiveness to TLR triggering and CD40 ligation. Mechanistically, miR-181a sustains ERK-MAPK signaling in mo-DCs, thereby enabling the maintenance of high levels of DC-SIGN and a high activation threshold. Low miR-181a levels during mo-DC differentiation, induced by inflammatory signals, do not support the high phospho-ERK signal transduction required for DC-SIGNhi mo-DCs and lead to development of proinflammatory DC-SIGNlo/- mo-DCs. Collectively, our study demonstrates that high DC-SIGN expression levels and a high activation threshold in mo-DCs are linked and simultaneously maintained by miR-181a.

ORGANISM(S): Homo sapiens

PROVIDER: GSE96847 | GEO | 2020/03/10

REPOSITORIES: GEO

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Homo sapiens

Project description:Identification of miR-181a target mRNAs by RIP-CHIP during terminal differentiation of DC-SIGN+ mo-DCs

| PRJNA379915 | ENA

NR4A3 plays a pivotal role in the differentiation of monocyte-derived dendritic cells

Project description:The molecular requirements that guide the differentiation of monocytes into macrophages or monocyte-derived dendritic cells (Mo-DCs) are poorly understood. Here, we demonstrate that the nuclear orphan receptor NR4A3 guides monocyte fate and is essential for Mo-DC differentiation. Nr4a3-/- mice are impaired in the in vivo generation of DC-SIGN+ Mo-DCs following LPS stimulation and, as such, are defective at priming a CD8+ T cell response to gram negative bacteria. We also demonstrate that NR4A3 is an essential downstream effector of IRF4 during in vitro differentiation of Mo-DCs with GM-CSF and IL-4 and that, in absence of NR4A3, monocytes are diverted to macrophages. Our transcriptomic analysis of the genes regulated by NR4A3 reveals that the acquisition of the Mo-DC differentiation program is intertwined with the acquisition of a migratory signature. Furthermore, NR4A3 is critical for steady-state migration of non-lymphoid tissue conventional DCs to lymph nodes. Altogether, our results highlight a unique role for NR4A3 in Mo-DC differentiation and in the acquisition of migratory properties.

2019-06-25 | GSE99837 | GEO

Transcription profiling of human monocyte derived dendritic cells treated with DC-SIGN initiates an immature dendritic cell phenotype triggering Rho activation that is utilised by HIV-1

Project description:DC-SIGN is a C-type lectin expressed by dendritic cells (DCs) that binds HIV-1, sequestering it within multivesicular bodies to facilitate transmission to CD4+ T cells. Here we characterize the molecular basis of signalling through DC-SIGN by large-scale gene expression profiling and phosphoproteome analysis. Solitary DC-SIGN activation leads to a phenotypically disparate transcriptional program from Toll-like receptor (TLR) triggering with downregulation of MHC II, CD86, and interferon response genes and with induction of the TLR negative regulator ATF3. Phosphoproteome analysis reveals DC-SIGN signals through the leukemia-associated Rho guanine nucleotide exchange factor (LARG) to induce Rho activity. This LARG activation also occurs on DC HIV exposure and is required for effective HIV viral synapse formation. Taken together HIV mediated DC-SIGN signalling provides a mechanism by which HIV evades the immune response yet induces viral spread. Experiment Overall Design: Circulating monocyte derived DCs were isolated from buffy coats by adherence and culture in IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF). DC preparations analyzed were more than 98% pure. At day four 10 million immature DCs were either left unstimulated or stimulated using plate bound anti-DC-SIGN antibody for 2 hr. Three replicates of non-stimulated or stimulated cells were taken and used to extract total RNA.

2008-06-14 | E-GEOD-6090 | biostudies-arrayexpress

DC-SIGN initiates an immature dendritic cell phenotype triggering Rho activation that is utilised by HIV-1

Project description:DC-SIGN is a C-type lectin expressed by dendritic cells (DCs) that binds HIV-1, sequestering it within multivesicular bodies to facilitate transmission to CD4+ T cells. Here we characterize the molecular basis of signalling through DC-SIGN by large-scale gene expression profiling and phosphoproteome analysis. Solitary DC-SIGN activation leads to a phenotypically disparate transcriptional program from Toll-like receptor (TLR) triggering with downregulation of MHC II, CD86, and interferon response genes and with induction of the TLR negative regulator ATF3. Phosphoproteome analysis reveals DC-SIGN signals through the leukemia-associated Rho guanine nucleotide exchange factor (LARG) to induce Rho activity. This LARG activation also occurs on DC HIV exposure and is required for effective HIV viral synapse formation. Taken together HIV mediated DC-SIGN signalling provides a mechanism by which HIV evades the immune response yet induces viral spread. Keywords: Activation state, signalling, Toll-like Receptor (TLR)

2007-04-24 | GSE6090 | GEO

miRNA expression patterns in immature and CpG stimulated murine BMDCs

Project description:Toll-like receptor (TLR)-induced maturation of dendritic cells (DCs) leads to the production of proinflammatory cytokines as well as the upregulation of various molecules involved in T cell activation. These are believed to be the critical events that account for the induction of the adaptive immune response. Here, we have examined the role of micro-RNA-155 (miR-155) in DC function and the induction of immunity. Using a model where the transfer of self-antigen-pulsed, TLR-matured DCs can induce a functional CD8 T cell response and autoimmunity, we find that DCs lacking miR-155 have an impaired ability to break immune tolerance. Importantly, transfer of self- antigen-pulsed DCs overexpressing miR-155 was sufficient to break tolerance in the absence of TLR stimuli. Although these unstimulated DCs induced T cell function in vivo, there was no evidence for the upregulation of costimulatory ligands or cytokine secretion. Further analysis showed that miR-155 influenced the level of the phosphatase SHIP1 in DCs, and that the lack of SHIP1 in DCs was sufficient to break T cell tolerance in vivo, again in the absence of TLR induced DC maturation. Our study demonstrates that the overexpression of miR-155 in DCs is a critical event that is alone sufficient to break self tolerance and promote a CD8-mediated autoimmune response in vivo. This process is independent of the induction of conventional DC maturation markers, indicating that miR-155 regulation of SHIP represents a unique axis that regulates DC function in vivo.

2015-09-04 | GSE72716 | GEO

Microarray expression data from WT and IRF4 KO Sirp-a+ DCs

Project description:Cross-presentation of cell-associated antigens is carried out by classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs), but whether a similar or distinct program exists for this process is unknown. In examining this issue, we discovered that only Ly-6ChiTremL4– monocytes, but not Ly-6ChiTremL4+ monocytes, can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4. However, Ly-6ChiTremL4+ monocytes were committed to Nur77-dependent development of Ly-6CloTremL4+ monocytes. Further, differentiation of monocytes with GM-CSF required addition of IL-4 to generate Zbtb46+ Mo-DCs that cross-presented as efficiently as CD24+ cDCs, which was accompanied by increased Batf3 and Irf4 expression. Unlike cDCs, Mo-DCs required only IRF4, and not Batf3, for cross-presentation. Further, Irf4–/– monocytes failed to develop into Zbtb46+ Mo-DCs, and instead developed into macrophages. Thus, cDCs and Mo-DCs use distinct transcriptional programs for cross-presentation that may drive different antigen-processing pathways. These differences may influence development of therapeutic DC vaccines based on Mo-DCs.

2016-05-25 | GSE75014 | GEO

Microarray expression data from circulating blood monocytes

2016-05-25 | GSE75013 | GEO

Microarray expression data from monocytes, Mo-DCs and CD24 DCs

2016-05-25 | GSE75012 | GEO

Simultaneous inhibition of PPAR-γ and mTORC1 enables GM-CSF to induce the differentiation of monocytes into highly immunogenic dendritic cells

Project description:Monocytes can differentiate into macrophages or dendritic cells. When treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) monocytes differentiate into macrophage-like cells. Here, we report that pharmacological blockade of the nuclear receptor PPARγ in monocytes turns GM-CSF into a potent inducer of dendritic cell (Mo-DC) differentiation. Remarkably, simultaneous blockade of PPARγ and mTORC1 in the presence of GM-CSF promoted the differentiation of Mo-DCs with a stronger phenotypic stability and immunogenic profile when compared with canonical Mo-DCs differentiated by treatment with GM-CSF and IL-4. Moreover, and in contrast with the observations made with GM-CSF and IL-4, blockade of PPARγ and mTORC1 was shown to be able to induce the differentiation of monocyte-derived macrophages (Mo-Macs) into Mo-DCs. Transcriptional profiling performed at either early time points, as well as at the end of the differentiation process, revealed marked differences in the gene expression signature between Mo-DCs induced by GM-CSF and IL-4 and Mo-DCs induced by GM-CSF in the presence of PPARγ and/or mTORC1 inhibitors, thus suggesting diverging differentiation pathways. Our observations might contribute, not only to a better understanding of the mechanisms involved in Mo-DCs differentiation but also to improving the efficacy of both, DC vaccines and therapies focusing on the modulation of myeloid cell functions.

2023-02-23 | GSE210935 | GEO

DC-SCRIPT binds GA-rich enhancers to control MAPK-signaling and IL-10 production in human dendritic cells

Project description:Dendritic cells (DCs) uniquely direct the adaptive immune response towards activation or inhibition, yet little is known how these opposite programs are regulated at the transcriptional level. Here we applied genome-wide approaches to delineate the molecular function of DC-Specific transCRIPT (DC-SCRIPT/ZNF366), an 11 Zn finger-containing transcription factor potentiating DC-function by limiting IL-10 production. Transcriptome analysis identified DC-SCRIPT to affect expression of genes involved in MAPK signaling, and ChIP-Seq analysis showed binding of DC-SCRIPT to GA-rich enhancers nearby genes encoding MAPK Dual-Specificity Phosphatases (DUSPs). Functional studies demonstrated that DC-SCRIPT-knockdown DCs express much less DUSP4 and exhibit increased phosphorylation of all the three major MAPKs (ERK, JNK and p38). Enhanced ERK signaling in DC-SCRIPT-knockdown DCs led to higher production of the immune-inhibitory cytokine IL-10, which could be reverted by DUSP4 overexpression. These results delineate the molecular mechanism DC-SCRIPT employs to limit IL-10 production in DCs, thereby fine-tuning these professional antigen-presenting cells towards immune activation.

2018-06-19 | GSE78923 | GEO

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