Rheumatology (Oxford, England) · 2025
Circulating cell-free DNA promotes inflammation in dermatomyositis patients with anti-NXP2 antibodies via the cGAS/STING pathway.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Wang Yikang, Zhao Yawen, Gang Qiang, Hao Hongjun, Gao Feng, Deng Jianwen, Wang Zhaoxia, Zhang Wei, Yuan Yun, Zheng Yiming
Аннотация
OBJECTIVES: DM is a rare type I IFN (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 the cGAS/STING pathway to induce IFN-I production in autoimmune diseases. We investigated whether serum-derived ccf-DNA had a pathogenic effect 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 reverse transcriptase quantitative polymerase chain reaction 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 colocalized 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. Reverse transcriptase quantitative polymerase chain reaction 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.
CONCLUSION: 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 identified a pathogenic effect of ccf-DNA on skeletal muscle via the cGAS/STING pathway.
METHODS: Serum ccf-DNA levels were measured, and correlations between ccf-DNA and clinicopathological indicators were performed. RNA sequencing, immunofluorescence, western blotting and reverse transcriptase quantitative polymerase chain reaction 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 colocalized 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. Reverse transcriptase quantitative polymerase chain reaction 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.
CONCLUSION: 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 identified a pathogenic effect of ccf-DNA on skeletal muscle via the cGAS/STING pathway.
Предметные рубрики MeSH
HumansNucleotidyltransferasesMembrane ProteinsCell-Free Nucleic AcidsFemaleMaleDermatomyositisMiddle AgedSignal TransductionAutoantibodiesAdultRNA-Binding ProteinsMuscle, SkeletalDNA-Binding ProteinsInflammationAdenosine TriphosphatasesSTING ProteinCyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase