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.

Nyckelord

Animals

Arthritis

Rheumatoid/*immunology/metabolism/pathology

B-Lymphocytes/metabolism

*CpG Islands

DNA Adducts

*DNA Damage

*DNA Methylation

DNA

Mitochondrial/*metabolism

Female

Humans

Macrophages/metabolism

Mice

Mice

Inbred BALB C

Mitochondria

Liver

Mitochondria

Muscle

Monocytes/metabolism

NF-kappa B/metabolism

Oligodeoxyribonucleotides/administration & dosage

Oxidation-Reduction

Synovial Fluid/chemistry

T-Lymphocytes/metabolism

Tumor Necrosis Factor-alpha/metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)