Circulating Cell-Free DNA Promotes Inflammation in Patients with Dermatomyositis with Anti-NXP2 Antibodies via the cGAS/STING Pathway.
Rheumatology (Oxford)
; 2024 Aug 07.
Article
em En
| MEDLINE
| ID: mdl-39110532
ABSTRACT
OBJECTIVES:
Dermatomyositis (DM) is a rare type I interferon (IFN-I)-driven autoimmune disease, and anti-nuclear matrix protein 2 (NXP2) antibody is related to severe muscle disease and poor prognosis. Circulating cell-free DNA (ccf-DNA), including ccf-mitochondrial DNA and ccf-nuclear DNA, activates cGAS/STING pathway to induce IFN-I production in autoimmune diseases. We investigated whether serum-derived ccf-DNA played a pathogenic role on skeletal muscle in anti-NXP2 antibody-positive DM.METHODS:
Serum ccf-DNA levels were measured, and correlations between ccf-DNA and clinicopathological indicators were performed. RNA sequencing, immunofluorescence, western blotting and RT-qPCR were performed on skeletal muscle samples. The serum-induced expression of p-STING in C2C12 cells was assessed in vitro.RESULTS:
We found that increased ccf-DNA levels were positively correlated with MYOACT scores in anti-NXP2 antibody-positive DM. RNA sequencing and immunofluorescence results revealed that the cytosolic DNA-sensing pathway was upregulated and that increased cytosolic dsDNA was colocalised with cGAS in skeletal muscle in anti-NXP2 antibody-positive DM. Western blot analysis revealed activation of the cGAS/STING pathway in patients with perifascicular atrophy (PFA) but not in patients without PFA. RT-qPCR showed increased IFN-I scores in both patients with PFA and patients without PFA. Sera from patients with PFA increased p-STING expression in C2C12 cells, and DNase I treatment and STING inhibitor efficiently inhibited p-STING expression, respectively.CONCLUSIONS:
Increased ccf-DNA levels may be potential biomarkers for monitoring disease activity in anti-NXP2 antibody-positive DM. Activation of the cGAS/STING pathway is associated with PFA. Our findings identify the pathogenic role of ccf-DNA on skeletal muscle via the cGAS/STING pathway.
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Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China