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

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Mitochondrial DNA (mtDNA) contains unmethylated CpG motifs and is susceptible to oxidative damage.
• The inflammatogenic potential of mtDNA in vivo and its specific role in arthritis pathogenesis remain incompletely understood.

Purpose of the Study:

• To investigate the inflammatogenic properties of mitochondrial DNA (mtDNA) in vitro and in vivo.
• To determine the mechanisms underlying mtDNA-induced inflammation and arthritis.
• To assess the presence of extracellular mtDNA in patients with rheumatoid arthritis.

Main Methods:

• Intra-articular injection of purified human and murine mtDNAs, oxidatively damaged oligonucleotides, and nuclear DNA into mice.
• Assessment of arthritis development and inflammatory responses.
• Analysis of B cell and T cell dependency, monocyte/macrophage mediation, and nuclear factor-kappaB (NF-κB) signaling pathways.
• Detection of extracellular mtDNA in synovial fluids of rheumatoid arthritis patients and control subjects.

Main Results:

• Intra-articular injection of mtDNA induced arthritis in mice, while nuclear DNA did not.
• Oligodeoxynucleotides with oxidatively damaged bases also induced arthritis.
• mtDNA-induced arthritis was mediated by monocytes/macrophages and involved NF-κB activation and tumor necrosis factor alpha (TNF-α) production.
• Extracellular mtDNA was found in the synovial fluid of rheumatoid arthritis patients but not in controls.

Conclusions:

• Endogenous mitochondrial DNA (mtDNA) possesses inflammatogenic properties mediated by unmethylated CpG motifs and oxidatively damaged adducts.
• mtDNA can induce arthritis through monocyte/macrophage activation and TNF-α production.
• Extracellular mtDNA may play a role in the pathogenesis of rheumatoid arthritis.