title: Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation.
abstract: 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.
authors.affiliation: Department of Genetics, Osaka University Medical School, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Okabe
authors.forename: Kohki
authors.initials: K
authors.lastname: Kawane
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: 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
chemical_list: D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D051193:Toll-Like Receptors; D016899:Interferon-beta; D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II