Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

Abstract

Cytoplasmic nucleic acids sensing through cGAS-STING-TBK1 pathway is crucial for the production of antiviral interferons (IFNs). IFN production can also be induced by lipopolysaccharide (LPS) stimulation through Toll-like receptor 4 (TLR4) in appropriate conditions. Of note, both IFN production and dysregulated LPS-response could play a role in the pathogenesis of Systemic Lupus Erythematosus (SLE). Indeed, LPS can trigger SLE in lupus-prone mice and bacterial infections can induce disease flares in human SLE. However, the interactions between cGAS and TLR4 pathways to IFNs have been poorly investigated. To address this issue, we studied LPS-stimulation in cellular models with a primed cGAS-STING-TBK1 pathway. cGAS-stimulation was naturally sustained by undigested self-nucleic acids in fibroblasts from DNase2-deficiency interferonopathy, whilst it was pharmacologically obtained by cGAMP-stimulation in THP1 cells and murine bone marrow-derived dendritic cells. We showed that cells with a primed cGAS-STING-TBK1 pathway displayed enhanced IFNs production after TLR4-challenge. STING-inhibition did not affect IFN production after LPS alone, but prevented the amplified IFN production in cGAMP-primed cells, suggesting that functional STING is required for priming-dependent enhancement. Furthermore, we speculated that an increased PIK3AP1 expression in DNase2-deficient fibroblasts may link cGAMP-priming with increased LPS-induced IFN production. We showed that both the hyper-expression of PIK3API and the enhanced LPS-induced IFN production can be contrasted by STING inhibitors. Our results may explain how bacterial LPS can synergize with cGAS-pathway in promoting the development of SLE-like autoimmunity.

The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity

“…We provide experimental evidence that STING1 forms a protein complex with MYD88, which is necessary for the inducible expression of ACOD1. These findings may also establish a model to explain the interaction of STING1 and TLR signaling in the production of pro-inflammatory cytokines during infection ( Tesser et al., 2021 ; Zeng et al., 2017 ). Although previous studies have shown that ACOD1 is implicated in the antiviral response ( Daniels et al., 2019 ; Ren et al., 2016 ), we did not observe that TLR3, TLR7, TLR8, and TLR9 ligands induce ACOD1 expression in human monocytes.…”

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

“…To address this point, we inhibited key players of the UPR and/or ISR, including PKR, IRE1, and GADD34 ( 24 ), by treating patients' T cells with the C16, 4μ8C, or Guanabenz inhibitors, respectively. In addition, the potential implication of mitophagy-mediated mitochondrial DNA in this process was investigated by treating the cells with H-151, an inhibitor of the cytosolic DNA sensor STING (stimulator of IFN genes protein) ( 54 ). Of the four inhibitors used, only C16, targeting PKR, could substantially reduce the type I IFN response associated with PSMC3 variants in these patients (Fig.…”

Signal strength of STING activation determines cytokine plasticity and cell death in human monocytes

“…Similar to our results with STING ligands, TLR7/8 ligand Resiquimod was also shown to inhibit IL-10 production in human monocytes 26 . In other studies, activation of cGAS/STING was found to inhibit TLR9-mediated production of type I IFN in human plasmacytoid dendritic cells 41 but to enhance LPS-induced type I IFN pathway activation in monocytic THP-1 cells and murine bone marrow derived dendritic cells 42 .…”