Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation.

Abstract

DNase II digests the chromosomal DNA in macrophages after apoptotic cells and nuclei from erythroid precursors are engulfed. The DNase II-null mice develop a polyarthritis that resembles rheumatoid arthritis. Here, we showed that when bone marrow cells from the DNase II-deficient mice were transferred to the wild-type mice, they developed arthritis. A deficiency of Rag2 or a lack of lymphocytes accelerated arthritis of the DNase II-null mice, suggesting that the DNase II(-/-) macrophages were responsible for triggering arthritis, and their lymphocytes worked protectively. A high level of TNFα, IL-1β, and IL-6 was found in the affected joints of the DNase II-null mice, suggesting an inflammatory-skewed cytokine storm was established in the joints. A lack of TNFα, IL-1β, or IL-6 gene blocked the expression of the other cytokine genes as well and inhibited the development of arthritis. Neutralization of TNFα, IL-1β, or IL-6 had a therapeutic effect on the developed arthritis of the DNase II-null mice, indicating that the cytokine storm was essential for the maintenance of arthritis in the DNase II-deficient mice. Methotrexate, an antimetabolite that is often used to treat patients with rheumatoid arthritis, had a therapeutic effect with the DNase II-null mice. These properties of arthritis in the DNase II-null mice were similar to those found in human systemic-onset juvenile idiopathic arthritis or Still's disease, indicating that the DNase II-null mice are a good animal model of this type of arthritis.

• Authors: Kohki Kawane, Hiromi Tanaka, Yusuke Kitahara, Shin Shimaoka, Shigekazu Nagata
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 45 Pg. 19432-7 (Nov 09 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20974942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• DNA
• Endodeoxyribonucleases
• deoxyribonuclease II
• Methotrexate

Topics

• Animals
• Arthritis (etiology)
• Cytokines (analysis)
• DNA (metabolism)
• Disease Models, Animal
• Endodeoxyribonucleases (deficiency)
• Lymphocytes (immunology)
• Macrophages (immunology)
• Methotrexate (pharmacology, therapeutic use)
• Mice
• Mice, Knockout