Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

C5aR2 regulates STING-mediated interferon beta production in human macrophages

ABSTRACT: The complement system mediates diverse regulatory effects across the immune system. C5aR2, an enigmatic receptor for anaphylatoxin C5a, has been shown to modulate PRR-dependent pro-inflammatory cytokine secretion in human macrophages. However, the specific downstream targets and underlying molecular mechanisms are less defined. In this study, CRISPR-Cas9 was used to generate macrophage models lacking C5aR2, which were used to probe the role of C5aR2 in the context of PRR stimulation. cGAS and STING-induced IFN-β secretion was significantly increased in C5aR2 KO THP-1 cells and C5aR2-edited primary human monocyte-derived macrophages, and expression of STING and IRF3 was increased in C5aR2 KO cell lines, implicating C5aR2 as a regulator of the IFN-β response to cGAS-STING pathway activation. Transcriptomic analysis by RNAseq revealed that nucleic acid sensing and antiviral signalling pathways were significantly up-regulated in C5aR2 KO THP-1 cell lines. These results suggest that C5aR2 is a negative regulator of nucleic acid sensing in macrophages, with potential relevance for viral infection and anti-tumour immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245973 | GEO | 2023/10/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II deficient mice

Project description:Innate immune PRRs sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. Here we utilize a model of inflammation resulting from accrual of self DNA (DNase II-/- Ifnar-/-) to understand the role of PRR sensing pathways in arthritis and autoantibody production. Using mice deficient in DNase II/Ifnar together with deficiency in either STING or AIM2 (TKO), we reveal central roles for the STING and AIM2 pathway in arthritis. AIM2 TKO mice show limited inflammasome activation and, like STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, while DNase II-/- Ifnar-/- mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid sensing pathways in disease manifestations.

2014-12-25 | GSE63503 | GEO

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [mRNA-seq]

Project description:Mutations in LMNA, encoding the nuclear lamina protein Lamin A/C, cause malignant dilated cardiomyopathy. A prevailing hypothesis postulates that LMNA mutations cause nuclear envelope ruptures that trigger pathogenic inflammation via the cGAS-STING cytosolic DNA-sensing pathway. Our study suggests that adult mouse cardiomyocytes are unable to activate the cGAS-STING pathway in response to nuclear envelope rupture and proposes that the cGAS-STING pathway is not a pathogenetic component of LMNA-related dilated cardiomyopathy in adult humans. The aim of this project is to investigate the contribution of the cGAS-STING cytosolic DNA-sensing pathway to a mouse model of LMNA-related dilated cardiomyopathy accompanied by nuclear envelope rupture.

2024-04-26 | GSE241577 | GEO

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [SLAM-IT-seq]

2024-04-26 | GSE241589 | GEO

The cGAS-STING pathway is dispensable in a mouse model of LMNA-cardiomyopathy despite nuclear envelope rupture [sci-RNA-seq]

2024-04-26 | GSE241587 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner II

Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact. Peritoneal macrophages from mutant and control mice were isolated by FACS. Total RNA was subjected to next generation mRNA sequencing.

2022-10-10 | GSE214712 | GEO

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner I

2022-10-10 | GSE214711 | GEO

Gene expression profiles in BMDM cells of Trex1-KO and wild-type mice after treatment of STING antagonists

Project description:Mounting evidence demonstrates that cGAS-STING signaling is the major pathway in sensing cytosolic DNAs. However, aberrant accumulation of self DNA molecules in Trex1 (a 3'-to-5' DNA exonuclease) deficient cells usually causes over-activation of cGAS-STING signaling, which is associated with the pathology of several autoimmune diseases. Here, we investigated gene expression changes in BMDM cells of Trex1 knockout mice after manipulating cGAS-STING signaling activity via treatment of two STING antagonists (SN-011 and H151) .

2021-05-26 | GSE143830 | GEO

cGAS maintains basal antiviral state

Project description:Upon recognition of aberrantly located DNA, the innate immune sensor cGAS activates STING/IRF-3-driven antiviral responses. Here we characterized the ability of a specific variant of the cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted towards the possibility for an additional binding site for a potential cellular co-factor in cGAS dimers. However, cGAS(WT) or cGAS(P261H)-reconstituted THP-1 cGAS KO cells shared steady-state expression of interferon-stimulated genes (ISGs), as opposed to cells expressing the enzymatically inactive cGAS(G212A/S213A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared to cGAS KO- or cGAS(G212A/S213A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared to cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend towards a slightly reduced type I IFN response as compared to PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a base-line antiviral state rendering cells more refractory to ISG-sensitive viral infections. rs610913 failed to grossly differ phenotypically from the wild-type gene, suggesting that cGAS(P261H) and wild-type cGAS share a similar ability to sense viral infections in vivo.

2022-05-25 | GSE203334 | GEO

Differential gene regulation downstream of murine Tmem173 variants

Project description:We report positional cloning and characterization of a novel Sting allele that fails to activate IFN production in the wild-derived mice of MOLF/Ei strain in response to HSV (Herpes Simplex Virus) and Listeria monocytogenes both in vitro and in vivo. We show that previously uncharacterized mutations in the N-terminal of STING are responsible for low levels of IFN due to failure of MOLF STING to respond to cytosolic STING agonists such as 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) or poly(deoxyadenylic-deoxythymidylic) acid (dAdT). Using Next-Generation Sequencing (NGS) for the analysis of DNA-responses in congenic C57BL6.StingMOLF/MOLF (MOLF STING) mouse macrophages, we show that these mutations in MOLF/Ei discriminate in responses between different STING agonists. Macrophages from C57BL6.StingB6/B6Â¬ (B6 STING), or B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. To examine differential gene regulation downstream of murine Tmem173 (STING) allelic variants. We stimulated macrophages from B6 mice congenic for MOLF STING; macrophages from B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. One replicate of RNA-seq reads after each stimulation provided. Conditions are peritoneal macrophages from B6 congenic mice expressing: B6 STING, MOLF STING, or STING KO stimulated with 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), poly(deoxyadenylic-deoxythymidylic) acid (dAdT), or no treatment. This constitutes a total of 12 reads analyzed in this data set.

2016-07-05 | E-GEOD-68140 | biostudies-arrayexpress

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner [2]

Project description:Loss of SAMHD1 causes chronic activaiton of the MDA5/MAVS dsRNA sensing pathway, only when cGAS/STING signaling is intact.

2022-08-18 | GSE211209 | GEO