Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses

被引:420
作者
Collins, LV
Hajizadeh, S
Holme, E
Jonsson, IM
Tarkowski, A
机构
[1] Gothenburg Univ, Dept Rheumatol & Inflammat Res, S-41346 Gothenburg, Sweden
[2] Sahlgrens Univ Hosp, Dept Clin Chem, S-41345 Gothenburg, Sweden
关键词
inflammation; rheumatoid arthritis; monocytes/macrophages;
D O I
10.1189/jlb.0703328
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
We report that mitochondrial DNA (mtDNA) is inflammatogenic in vitro and in vivo as a result of the presence of unmethylated CpG sequences and its oxidative status. Purified human and murine mtDNAs induced arthritis when injected intra-articularly (i.a.) in mice. Importantly, oligodeoxynucleotide that contained a single oxidatively damaged base also induced arthritis when injected i.a. in mice. In contrast, neither human nor murine nuclear DNA induced inflammation. mtDNA-induced arthritis was neither B cell- nor T cell-dependent but was mediated by monocytes/ macrophages. mtDNA-induced nuclear factor-kappaB stimulation resulted in the production of tumor necrosis factor alpha, a potent, arthritogenic factor. Finally, extracellular mtDNA was detected in the synovial fluids of rheumatoid arthritis patients but not of control subjects. We conclude that endogenous mtDNA displays inflammatogenic properties as a result of its content of unmethylated CpG motifs and oxidatively damaged adducts.
引用
收藏
页码:995 / 1000
页数:6
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