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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0703328

Received for publication July 16, 2003.
Revised January 11, 2004.
Accepted for publication January 13, 2004.

Article

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

L. Vincent Collins *@, Shahin Hajizadeh *, Elisabeth Holme {dagger}, Ing-Marie Jonsson *, and Andrej Tarkowski *

*Department of Rheumatology and Inflammation Research, University of Göteborg, Sweden; and {dagger}Department of Clinical Chemistry, Sahlgrenska University Hospital, Göteborg, Sweden

@ To whom correspondence should be addressed. E-mail: vincent.collins{at}rheuma.gu.se.


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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. It is important that an 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. It is important that mtDNA-induced nuclear factor-{kappa}B 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.

Key Words: inflammation • rheumatoid arthritis • monocytes/macrophages




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