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

Yasutaka Okabe1, Kohki Kawane, Shizuo Akira

  • 1Department of Genetics, Osaka University Medical School, Japan.

The Journal of Experimental Medicine
|November 23, 2005
PubMed

Insights

Deoxyribonuclease II deficiency in mice causes undigested DNA accumulation, leading to innate immune activation and embryonic lethality. This innate immune response is independent of Toll-like receptors, indicating a novel DNA sensing pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Deoxyribonuclease II (DNase II) is crucial for degrading DNA from apoptotic cells and expelled nuclei within macrophages.
  • DNase II deficiency in mice leads to embryonic lethality due to uncontrolled DNA accumulation and subsequent interferon beta (IFNbeta) gene activation.

Purpose of the Study:

  • To investigate the innate immune sensing mechanism activated by undigested DNA in DNase II-deficient macrophages.
  • To determine the role of Toll-like receptors (TLRs) in the lethality observed in DNase II(-/-) mice.

Main Methods:

  • Analysis of cytokine and IFN-inducible gene expression in DNase II-deficient fetal liver macrophages and fibroblasts.
  • Assessment of gene expression in macrophages and fibroblasts after engulfing apoptotic cells.
  • Evaluation of the impact of ablating TLR3, TLR9, MyD88, and TRIF on the survival of DNase II(-/-) mice.

Main Results:

  • DNase II(-/-) macrophages specifically produce inflammatory cytokines like IFNbeta, TNFalpha, and CXCL10.
  • IFN-inducible genes are expressed in both macrophages and other cell types in DNase II(-/-) embryos.
  • Engulfment of apoptotic cells by DNase II(-/-) cells triggers IFNbeta and CXCL10 expression.
  • Lethality in DNase II(-/-) mice is not affected by the absence of TLR3, TLR9, MyD88, or TRIF.

Conclusions:

  • A Toll-like receptor (TLR)-independent mechanism senses endogenous DNA that escapes lysosomal degradation.
  • This sensing pathway activates innate immunity, contributing to the embryonic lethality observed in DNase II deficiency.

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