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

被引:21
|
作者
Tesser, Alessandra [1 ]
Piperno, Giulia Maria [2 ]
Pin, Alessia [1 ]
Piscianz, Elisa [1 ]
Boz, Valentina [3 ]
Benvenuti, Federica [2 ]
Tommasini, Alberto [1 ,3 ]
机构
[1] IRCCS Burlo Garofolo, Dept Pediat, Inst Maternal & Child Hlth, I-34137 Trieste, Italy
[2] Int Ctr Genet Engn & Biotechnol ICGEB, I-34149 Trieste, Italy
[3] Univ Trieste, Dept Med Surg & Hlth Sci, I-34149 Trieste, Italy
关键词
type I interferons; Toll-like receptor 4; DNase2-deficiency; interferonopathy; Systemic Lupus Erythematosus; CYCLIC GMP-AMP; B-CELL ADAPTER; GENE-EXPRESSION; DENDRITIC CELLS; DNA SENSOR; BCAP; ACTIVATION; MONOCYTES; SYNTHASE; IMMUNITY;
D O I
10.3390/cells10040785
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:12
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