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

• Published in: Journal of leukocyte biology Vol. 75; no. 6; pp. 995 - 1000
• Main Authors: Collins, L. Vincent, Hajizadeh, Shahin, Holme, Elisabeth, Jonsson, Ing‐Marie, Tarkowski, Andrej
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.06.2004
• Subjects: Animals; Arthritis; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; B-Lymphocytes - metabolism; CpG Islands; DNA; DNA Adducts; DNA Damage; DNA Methylation; DNA, Mitochondrial - metabolism; Female; Humans; In Vitro Techniques; Inbred BALB C; inflammation; Liver; Macrophages - metabolism; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondria, Liver; Mitochondria, Muscle; Mitochondrial/metabolism; Monocytes - metabolism; monocytes/macrophages; Muscle; NF-kappa B - metabolism; Oligodeoxyribonucleotides - administration & dosage; Oxidation-Reduction; rheumatoid arthritis; Rheumatoid/immunology/metabolism/pathology; Synovial Fluid - chemistry; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0703328

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‐κB stimulation resulted in the production of tumor necrosis factor α, 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.