August 2012 Lethal anemia and chronic polyarthritis caused by undigested mammalian DNA

Lethal anemia and chronic polyarthritis caused by undigested mammalian DNA

  B6.129-Dnase2atm2Osa/OsaRbrc RBRC04020
B6.129-Dnase2atm1Osa Ifnar1tm1Agt/OsaRbrc RBRC04021
Lethal anemia and chronic polyarthritis caused by undigested mammalian DNA
Courtesy of Dr. Shigekazu Nagata, Kyoto University

E17.5 wild-type, DNase2a-/- (DNase II-/-), and DNase2a-/-Ifnar1-/- (DNase II-/-IFN-IR-/-) embryos are dissected free from the yolk sac. The DNase2a-/- embryos appear normal except for severe anemia. Anemia is not seen in the DNase2a-/-Ifnar1-/- embryos, confirming that type I interferon produced in the DNase2a-/- embryos causes the anemia.


Lysosomes in macrophages carry various degrading enzymes that digest the cellular components of dead cells. DNase II is a deoxyribonuclease that digests DNA and has optimal activity under acidic condition. A large amount of undigested DNA is observed in macrophages in the fetal liver of DNase2a-/- mouse embryos and in the bone marrow of inducible DNase2a-deficient mice. Undigested DNA in the lysosomes activates macrophages to produce interferon-β, which causes lethal anemia in DNase2a-/- embryos. Indeed, on E17.5, the number of red blood cells in DNase2a-/- embryos is less than 10% of that observed in wild-type embryos [1, 2].


Inducible DNase2a-deficient mice and double-mutant mice lacking DNase II and the type I interferon receptor both appear normal at birth, but develop chronic polyarthritis resembling human rheumatoid arthritis [2, 3]. Histology of the affected joints shows cartilage destruction accompanied by the formation of a pannus-like structure. Genes for inflammatory cytokines, including TNF-α, IL-1β, and IL-6, are activated in the joints, and the administration of antibodies against these cytokines prevents the disease [4]. These mice provide the opportunity to understand the role of DNase II in the pathogenesis of human arthritis.


Related strain : B6;129-Dnase2atm1Osa/OsaRbrc RBRC01725
Depositor : Dr. Shigekazu Nagata
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University
References : [1]Kawane K, Fukuyama H, Kondoh G, Takeda J, Ohsawa Y, Uchiyama Y, Nagata S. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science; 292(5521):1546-9, 2001.
[2]Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature; 443(7114):998-1002, 2006.
[3]Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat Immunol; 6(1):49-56, 2005.
[4]Kawane K, Tanaka H, Kitahara Y, Shimaoka S, Nagata S. Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation. Proc Natl Acad Sci USA; 107(45):19432-7, 2010..

August 2012

contact: Shinya Ayabe, Ph.D.
Experimental Animal Division, RIKEN BioResource Center

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