A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance
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ABSTRACT:
PROVIDER: PRJNA926629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23194224_1.fastq.gz | Fastqsanger.gz | |||
| SRR23194224_2.fastq.gz | Fastqsanger.gz | |||
| SRR23194225_1.fastq.gz | Fastqsanger.gz | |||
| SRR23194225_2.fastq.gz | Fastqsanger.gz |
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Project description:Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.
2025-01-30 | GSE223519 | GEO
Project description:Cyclic dinucleotide stimulation of Nematostella vectensis
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Project description:In mammals, the cGAS-cGAMP-STING pathway is crucial for sensing viral infection and initiating an anti-viral type I interferon response. cGAS and STING are highly conserved genes that originated in bacteria and are present in most animals. By contrast, interferons only emerged in vertebrates; thus, the function of STING in invertebrates is unclear. Here, we use the STING ligand 2'3'-cGAMP to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 2'3'-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes, including the conserved transcription factor NF-κB. Knockdown experiments identified a role for NF-κB in specifically inducing anti-bacterial genes downstream of 2'3'-cGAMP, and some of these genes were also found to be induced during Pseudomonas aeruginosa infection. Furthermore, we characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work describes an unexpected role of a cGAMP sensing pathway in anti-bacterial immunity and suggests that a broad transcriptional response is an evolutionarily ancestral output of 2'3'-cGAMP signaling in animals.
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Project description:The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage. Cytosolic DNA triggers immune responses by activating the cGAS/STING pathway. The binding of DNA to the cytosolic enzyme cGAMP synthase (cGAS), activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic[G(2’,5’)pA(3’,5’)] (2’3’-cGAMP). 2’3’-cGAMP, a cyclic dinucleotide (CDN), activates the protein ‘stimulator of interferon genes’ (STING), which in turn activates the transcription factors IRF3 and NF-κB promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2’3’-cGAMP produced by malignant cells and other CDNs, including CDNs produced by bacteria and synthetic CDNs used in cancer immunotherapy, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter for CDNs. CDN uptake and functional responses are inhibited by depleting SLC19A1 from human cells and enhanced by overexpressing SLC19A1. In both human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates, as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer, host responsiveness to CDN-producing pathogenic microorganisms, and potentially in certain inflammatory diseases.
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Project description:Cyclic dinucleotides serve as bacterial secondary messengers regulating sporulation, motility, biofilm formation and virulence. A nonsymmetric c-di-GAMP is firstly identified in bacteria to promote colonization, while mammalian 2’3’-cGAMP is synthesized by cGAS through binding and activating STING to trigger innate immune activation. However, pathophysiological function of 2’3’-cGAMP beyond innate immunity remains elusive. Here, we report 2’3’-cGAMP facilitates cell migration independent of STING and its innate immune function. 2’3’-cGAMP interactome analysis with a targeted shRNA-screen identifies the GTPase Rab18 as a direct 2’3’-cGAMP binding partner and effector in cell migration control. Mechanistically, 2’3’-cGAMP binds Rab18-S17, E36 and R92 residues to facilitate Rab18 activation and subsequently promotes FosB transcription in promoting cell migration. Low-dose doxorubicin induces 2’3’-cGAMP synthesis and facilitates cell migration in vitro and in vivo. Interestingly, lovastatin induces Rab18 phosphorylation abolishes 2’3’-cGAMP recognition to antagonize 2’3’-cGAMP induced cell migration. Together, our study reveals a novel 2’3’-cGAMP function in cell migration control beyond innate immunity via binding Rab18 that provides new insights into clinical applications of 2’3’-cGAMP.
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Project description:The volume-regulated anion channel (VRAC) is a hexameric complex formed by LRRC8 proteins. VRACs are responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling by mediating the efflux of chloride. Besides chloride, LRRC8 proteins transport other molecules including immunomodulatory cyclic dinucleotides (CDNs) such as 2’3’cGAMP. Here we identify LRRC8C as a critical component of VRACs in T cells, where its deletion abolishes VRAC currents and RVD. We find that LRRC8C mediates the transport of 2’3’cGAMP in T cells. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production in vitro and enhanced T cell mediated immunity in vivo. We used RNA sequencing of CD4+ T cells from wild-type (WT) and Lrrc8c-/- mice to determine the effects of impaired cGAMP signaling in T cells. T cells of Lrrc8c-/- mice had impaired p53 signaling which was associated with decreased p53 expression. We found that uptake of 2’3’cGAMP and other CDNs via LRRC8C results in STING activation and p53 accumulation. Inhibition of STING in WT T cells recapitulates the phenotype of LRRC8C-deficient T cells whereas overexpression of p53 inhibits enhanced T cell function in the absence of LRRC8C. These findings establish cGAMP uptake through LRRC8C and subsequent STING-p53 signaling as a novel inhibitory signaling pathway in T cells and adaptive immunity.
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Project description:DNA sensing is a fundamental process in the immune system, including host defence against viruses. The DNA sensor cGAS synthesises 2’3’ cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which subsequently induces innate immunity. cGAMP not only activates STING in the cell where it is produced but also transfers to other cells. Transporters, channels and pores including SLC19A1, the SLC46A family, P2X7, ABCC1 and volume-regulated anion channels (VRACs) release cGAMP into the extracellular space and/or import cGAMP into cells. Emerging evidence suggests these proteins are important in antiviral immunity. Here, we investigated whether viruses antagonise cGAMP transporters, channels and pores. We report that infection with multiple human viruses depleted cGAMP conduits from cells. This included herpes simplex virus 1 (HSV-1) that targeted the VRAC subunits LRRC8A and LRRC8C, as well as SLC46A2 and P2X7, for degradation. The HSV-1 protein UL56 was required and sufficient for these effects that were mediated at least partially by proteasomal turnover. UL56 thereby inhibited the cGAMP uptake via VRAC, SLC46A2 and P2X7. Taken together, we show that HSV-1 actively antagonises cGAMP transfer across the plasma membrane and propose this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.
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