The Journal of Experimental Medicine
Keystone Symposia
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Published 21 November 2005. doi:10.1084/jem.20051654
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 10, 1333-1339
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ARTICLE

 Toll-like receptor–independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation

Yasutaka Okabe1, Kohki Kawane1,2, Shizuo Akira3, Tadatsugu Taniguchi4, and Shigekazu Nagata1,2,5

1 Department of Genetics, Osaka University Medical School
2 Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences
3 Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871
4 Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
5 Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan

CORRESPONDENCE Shigekazu Nagata: nagata{at}genetic.med.osaka-u.ac.jp

Deoxyribonuclease (DNase) II in macrophages cleaves the DNA of engulfed apoptotic cells and of nuclei expelled from erythroid precursor cells. DNase II–deficient mouse embryos accumulate undigested DNA in macrophages, and die in feto because of the activation of the interferon ß (IFNß) gene. Here, we found that the F4/80-positive macrophages in DNase II–/– fetal liver specifically produce a set of cytokines such as IFNß, TNF{alpha}, and CXCL10. Whereas, IFN-inducible genes (2'5'-oligo(A) synthetase, IRF7, and ISG15) were expressed not only in macrophages but also in other F4/80-negative cells. When DNase II–/– macrophages or embryonal fibroblasts engulfed apoptotic cells, they expressed the IFNß and CXCL10 genes. The ablation of Toll-like receptor (TLR) 3 and 9, or their adaptor molecules (MyD88 and TRIF), had no effect on the lethality of the DNase II–/– mice. These results indicate that there is a TLR-independent sensing mechanism to activate the innate immunity for the endogenous DNA escaping lysosomal degradation.

Abbreviations used: IRF3, IFN regulatory factor 3; MACS, magnetic-activated cell sorting; MEF, mouse embryonal fibroblast; TLR, Toll-like receptor; TRIF, Toll/IL-1 receptor domain-containing adaptor inducing IFN-ß.


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