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

LV Collins, S Hajizadeh, E Holme… - Journal of Leucocyte …, 2004 - academic.oup.com
LV Collins, S Hajizadeh, E Holme, IM Jonsson, A Tarkowski
Journal of Leucocyte Biology, 2004academic.oup.com
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 (ia) in mice. Importantly,
oligodeoxynucleotide that contained a single oxidatively damaged base also induced
arthritis when injected ia in mice. In contrast, neither human nor murine nuclear DNA
induced inflammation. mtDNA-induced arthritis was neither B cell-nor T cell-dependent but …
Abstract
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.
Oxford University Press