Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages.

Abstract

A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis. DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them. Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-alpha was upregulated in the bone marrow, and administration of anti-TNF-alpha antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-alpha, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.

• Authors: Kohki Kawane, Mayumi Ohtani, Keiko Miwa, Takuji Kizawa, Yoshiyuki Kanbara, Yoshichika Yoshioka, Hideki Yoshikawa, Shigekazu Nagata
• Journal: Nature (Nature) Vol. 443 Issue 7114 Pg. 998-1002 (Oct 26 2006) ISSN: 1476-4687 [Electronic] England
• PMID: 17066036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Interferon
• DNA
• Endodeoxyribonucleases
• deoxyribonuclease II

Topics

• Animals
• Arthritis (genetics, metabolism)
• Autoimmune Diseases (genetics, metabolism)
• Chronic Disease
• DNA (blood, metabolism)
• Endodeoxyribonucleases (deficiency, genetics, metabolism)
• Female
• Macrophages (metabolism)
• Male
• Mice
• Receptors, Interferon (deficiency, genetics, metabolism)