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(IFN beta) gene. Here, we found that the F4/80-positive macrophages in DNase II-/- fetal liver specifically produce a set of cytokines such as IFN beta, 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 IFN beta 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.