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

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-/-IF...

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Bibliographic Details
Published in:Nature 2006-10, Vol.443 (7114), p.998-1002
Main Authors: Nagata, Shigekazu, Kawane, Kohki, Ohtani, Mayumi, Miwa, Keiko, Kizawa, Takuji, Kanbara, Yoshiyuki, Yoshioka, Yoshichika, Yoshikawa, Hideki
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Arthritis
Arthritis - genetics
Arthritis - metabolism
Autoimmune Diseases - genetics
Autoimmune Diseases - metabolism
Biological and medical sciences
Bone marrow
Chronic Disease
Deoxyribonucleic acid
Diseases of the osteoarticular system
DNA
DNA - blood
DNA - metabolism
Endodeoxyribonucleases - deficiency
Endodeoxyribonucleases - genetics
Endodeoxyribonucleases - metabolism
Enzymes
Female
Humanities and Social Sciences
Inflammatory joint diseases
letter
Macrophages - metabolism
Male
Mammals
Medical sciences
Mice
multidisciplinary
Peptides
Receptors, Interferon - deficiency
Receptors, Interferon - genetics
Receptors, Interferon - metabolism
Rheumatoid arthritis
Rodents
Science
Science (multidisciplinary)
Tumors
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Summary: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)- was upregulated in the bone marrow, and administration of anti-TNF- 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- , which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.
ISSN:0028-0836
1476-4687
1476-4679
DOI:10.1038/nature05245