Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses.
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.
Collins
L Vincent
LV
University of Göteborg, Guldhedsgatan 10A, 41346 Göteborg, Sweden. vincent.collins@rheuma.gu.se
Hajizadeh
Shahin
S
Holme
Elisabeth
E
Jonsson
Ing-Marie
IM
Tarkowski
Andrej
A
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000378:metabolism; D018899:CpG Islands; D018736:DNA Adducts; D004249:DNA Damage; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver; D008931:Mitochondria, Muscle; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D010084:Oxidation-Reduction; D013582:Synovial Fluid / Q000737:chemistry; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018736:DNA Adducts; D004272:DNA, Mitochondrial; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha