Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain
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ABSTRACT:
PROVIDER: PRJNA992544 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25205174.fastq.gz | Fastqsanger.gz | |||
| SRR25205175.fastq.gz | Fastqsanger.gz | |||
| SRR25205176.fastq.gz | Fastqsanger.gz | |||
| SRR25205177.fastq.gz | Fastqsanger.gz | |||
| SRR25205178.fastq.gz | Fastqsanger.gz |
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Project description:E. fischeriana has long been used as a traditional Chinese medicine.Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrate that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA-seq analysis revealed that Dpo synergized the induction of ISGs by viral infection. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7 or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection.
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Project description:Stimulator of Interferon Genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFN and IFN-I Interferon Stimulated Genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to RANKL in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation settings, we sought to determine whether basal STING signaling contributes to bone homeostasis, an unexplored area. Using whole-body and myeloid-specific deficiency, we show that STING signaling prevents trabecular bone loss in mice over time and that myeloid-restricted STING activity is sufficient for this effect. STING-deficient osteoclast precursors differentiate with greater efficiency than wildtypes. RNA sequencing of wildtype and STING-deficient osteoclast precursor cells and differentiating osteoclasts reveals novel clusters of ISGs including a previously undescribed ISG set expressed in RANKL naïve precursors (tonic expression) and downregulated during differentiation. We identify a 50 gene tonic ISG signature that is STING-dependent and shapes osteoclast differentiation. From this list, we identify Interferon Stimulated Gene 15 (ISG15) as a tonic STING-regulated ISG that limits osteoclast formation. Thus, STING is an important upstream regulator of tonic IFN-I signatures shaping the commitment to osteoclast fates, providing evidence for a nuanced and novel role for this pathway in bone homeostasis.
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Project description:Activation of interferon-stimulated gene (ISG) responses is critical for control of viral infection. We recently identified that stimulation of the NLRP3 inflammasome and mobilization of the inflammatory cytokine IL-1β act as critical host restrictive pathways against West Nile virus (WNV) in a mechanism dependent on the regulation of ISGs. In order to define the mechanism by which IL-1β regulates these antiviral immune programs, we utilized global transcriptome analysis in myeloid cells, known targets of WNV replication to define gene signatures required for IL-1β driven antiviral responses. Surprisingly, we found IL-1β dependent activation of interferon-beta (IFN-β) and ISGs at late times following IL-1β treatment. Expression of these antiviral innate immune genes was found to be dependent on activation of IRF3 and appears to reflect a general shift in IL-1β signaling from an inflammatory response early following treatment to an anti-inflammatory type-I IFN mediated response at later times post-treatment. These data demonstrate that inflammatory and antiviral signals integrate to control viral infection. Strategies to co-opt these cytokine activated antiviral signatures can act as novel targeted therapeutic strategies tailored specifically to individual pathogens.
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Project description:Stimulator of interferon genes (STING), the central hub protein of the cGAS-STING signaling, is essential for type I IFN production of innate immunity. However, prolonged or excessive activation of STING is highly related to autoimmune diseases, most of which exhibit the hallmark of elevated expression of type I interferons and IFN-stimulated genes (ISGs). Thus, the activity of STING must be stringently controlled to maintain immune homeostasis. Here, we reported that CK1α, a protein serine/threonine kinase, was essential to prevent the over-activation of STING-mediated type I IFN signaling through autophagic degradation of STING. Mechanistically, CK1α interacted with STING upon the cGAS-STING pathway activation and promoted STING autophagic degradation by enhancing the phosphorylation of p62 at serine 349, which was critical for p62 mediated STING autophagic degradation. Consistently, SSTC3, a selective CK1α agonist, significantly attenuated the response of the cGAS-STING signaling by promoting STING autophagic degradation. Importantly, pharmaceutical activation of CK1α using SSTC3 markedly repressed the systemic autoinflammatory responses in the Trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CK1α in the autophagic degradation of STING to maintain immune homeostasis. Manipulating CK1α through SSTC3 might be a potential therapeutic strategy for alleviating STING-mediated aberrant type I IFNs in autoimmune diseases.
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