Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation.
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 beta (IFNbeta) gene. Here, we found that the F4/80-positive macrophages in DNase II(-/-) fetal liver specifically produce a set of cytokines such as IFNbeta, TNFalpha, 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 IFNbeta 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.
Okabe
Yasutaka
Y
Department of Genetics, Osaka University Medical School, Japan.
Kawane
Kohki
K
Akira
Shizuo
S
Taniguchi
Tadatsugu
T
Nagata
Shigekazu
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051193:Toll-Like Receptors / Q000502:physiology*; D015533:Transcriptional Activation
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D051193:Toll-Like Receptors; D016899:Interferon-beta; D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II