cGAS/STING signaling in the regulation of rheumatoid synovial aggression

Abstract

Background: Fibroblast-like synoviocytes (FLSs) play a critical role in promoting synovial aggression and joint destruction in rheumatoid arthritis (RA). Cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling plays an important role in controlling a series of cellular biological processes. However, it is still unclear whether cGAS/STING signaling regulates rheumatoid synovial aggression.Methods: Cell migration and invasion were detected using a Transwell chamber. Gene expression was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and protein expression was detected by western blotting. Reactive oxygen species (ROS) levels were measured by 2',7'-di chlorodihydrofluorescein diacetate (DCFH-DA) probe. F-actin staining and immunofluorescence assays were used to investigate lamellipodia formation and nuclear translocation, respectively. A severe combined immunodeficiency (SCID) mouse model was established to observe the migration and invasion of RA FLSs in vivo.Results: Our results showed that cytosolic double-stranded DNA (dsDNA)-induced cGAS/STING activation promoted the in vitro migration and invasion of RA FLSs. Moreover, RA FLSs treated with cGAS or STING short hairpin RNA (shRNA) exhibited reduced invasion into cartilage in the SCID model.Mechanistically, we determined that cGAS/STING activation leads to increased mitochondrial ROS levels, and thereby increases phosphorylation of mammalian sterile 20-like kinase 1 (MST1), a core component of the Hippo pathway, subsequently promoting activation of forkhead box1 (FOXO1). MST1 and FOXO1 knockdown also diminished the migration and invasion of RA FLSs.Conclusions: Our findings suggest that cGAS/STING signaling has an important role in regulating rheumatoid synovial aggression and that targeting cGAS/STING may represent a novel potential therapy for RA.

AXL Inhibits Proinflammatory Factors to Relieve Rheumatoid Arthritis Pain by Regulating the TLR4/NF-κB Signaling Pathway

“…RT-qPCR was performed as previously described [ 21 ]. Total RNA of tissue or cell was extracted using TRIzol reagent (Invitrogen, Waltham, MA, USA).…”

Role of reactive oxygen species and mitochondrial damage in rheumatoid arthritis and targeted drugs

“…The activation of the cGAS/STING pathway causes ROS accumulation and mitochondrial damage and promotes the migration and invasion of RA-FLSs, a process associated with the activation of the Hippo pathway. The knockdown of FOXO1 and MST1 , key genes of the Hippo pathway, significantly inhibits the migration and invasion of RA-FLSs ( 161 ). The cGAS/STING pathway plays a key role in the chronic inflammatory network by activating NF-κB and NLRP3 to promote the production of multiple inflammatory factors ( 162 ).…”

Potential Therapeutic Value of the STING Inhibitors

“…cGAS expression was elevated in RA-FLS, promoting their proliferation and enhancing TNF-α-mediated inflammation [ 259 ]. Likewise, the accumulation of dsDNA contributed to FLS-mediated rheumatoid arthritis synovial inflammation, which can be alleviated by the knockdown of cGAS or STING [ 260 , 261 ]. Additionally, TNF also results in joint swelling by inducing IFN response through the cGAS-STING pathway [ 262 ].…”