Single-cell analysis reveals stochastic regulation of type I IFN production by plasmacytoid dendritic cells and identifies host-derived environmental cues as amplifier of type I IFN production
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ABSTRACT:
PROVIDER: PRJNA474920 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7271290_1.fastq.gz | Fastqsanger.gz | |||
| SRR7271290_2.fastq.gz | Fastqsanger.gz | |||
| SRR7271291_1.fastq.gz | Fastqsanger.gz | |||
| SRR7271291_2.fastq.gz | Fastqsanger.gz | |||
| SRR7271292_1.fastq.gz | Fastqsanger.gz |
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Project description:Type I interferon (IFN) is a key driver of immunity to infections and cancer. Plasmacytoid dendritic cells (pDCs) are uniquely equipped to produce large quantities of type I IFN but the mech-anisms that control this process are poorly understood. Here, we developed a droplet-based microfluidic platform and investigated type I IFN production in human pDCs at the single-cell level. We show that type I IFN but not TNF alpha production is limited to a small subpopulation of individually stimulated pDCs and controlled by stochastic gene regulation. Combining single-cell cytokine analysis with single-cell RNA-seq profiling reveals no evidence for a pre-existing subset of type I IFN-producing pDCs. Intriguingly, by modulating the droplet microenvironment, we demonstrate that vigorous pDC population responses are driven by a type I IFN amplification loop. Our study highlights the significance of stochastic gene regulation and suggests strategies to dissect the characteristics of immune responses at the single-cell level.
2018-08-22 | GSE114161 | GEO
Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
2020-05-23 | GSE149415 | GEO
Project description:Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
2020-05-23 | GSE148902 | GEO
Project description:Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Afterwards, signal termination is achieved through autophagic degradation of STING, or STING recycling by retrograde COPI-mediated transport. Here we identify the GTPase ARF1 as a negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene production. Expression of patient-derived, GTPase-defective, ARF1 in cell lines and primary cells results in increased cGAS-STING dependent type I IFN signalling. Mechanistically, mutated ARF1 both induces activation of cGAS by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective COPI retrograde transport. Our data establish ARF1 as a key factor in cGAS-STING homeostasis, which is required to maintain mitochondrial integrity and promote STING recycling.
2022-06-23 | MSV000089711 | MassIVE
Project description:The RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) by increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through stimulator of IFN genes/type I IFN (STING/IFN-I) signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine that significantly improved the therapeutic effect of RT and radioimmunotherapy in a murine melanoma model. Our findings reveal a layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.
2024-10-29 | GSE272204 | GEO
Project description:Interferons (IFN) are induced by sensing of self and non-self RNA or DNA by pathogen recognition receptors. In particular, the aberrant accumulation of cytosolic nucleic acids or the accumulation of DNA lesions has the potential to activate the STING pathway to induce IFNs. While aberrant self-DNA sensing can cause autoimmunity, negative regulators keep these under check. Here we report that MEF2A is a novel negative regulator of inflammation which suppresses the induction of IFNs at homeostasis. We show that MEF2A deficiency results in the spontaneous induction of type I IFN and robust downstream ISG expression in a STING-dependent and cGAS-independent manner. We demonstrate that the IFN response elicited by MEF2A depletion could protect cells from cardiotropic virus infections. We found that the loss of MEF2A triggered the replicative stress response to promote a DDX41/STING-dependent induction type I IFN response. The replicative stress response is dependent on ATR kinase activity, as inhibition of ATR abrogated STING activation and type I IFN production. Thus, our study connects MEF2A with protection from maladaptive type I IFN responses due to replicative stress response across various cell types as well as links the DDX41-dependent activation of STING to the replicative stress response.
2023-10-01 | GSE209601 | GEO
Project description:CXCL10 is a chemokine induced by IFN-γ and implicated in the pathogenesis of type 1 diabetes (T1D). It attracts IFN-γ-producing T cells to the pancreatic islets, forming a positive feed-forward loop where T cells induce CXCL10 and attract themselves, but it is unclear what attracts the first IFN-γ-producing T cells in islets. Lipopolysaccharide induced CXCL10 production in cultured islets of nonobese diabetic (NOD) mice, and the lack of its inhibition in islets from NOD mice deficient for RAG1 or IFN-g receptor revealed its dissociation from the requirement of T cells and IFN-γ. To further investigate the mechanism of LPS induced CXCL10 production, the gene expression profile of pancreatic beta cells after culture of whole islets in LPS was analysed. Overall a gene expression signature of cytokine signalling, particularly by type I IFNs and TLR4 was upregulated after culture of islets in LPS.
2023-03-07 | GSE218698 | GEO
Project description:Type I Inter ferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their exceptional IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.
2025-01-05 | GSE285874 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE37222: c-Myc is a universal amplifier of gene expression [Microarray] GSE37229: c-Myc is a universal amplifier of gene expression [ChIP-Seq] Refer to individual Series
2012-09-27 | E-GEOD-37230 | biostudies-arrayexpress
Project description:YTHDF1 loss in dendritic cells potentiates radiationinduced antitumor immunity via STING-dependent type I IFN production
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