Editors' ChoiceInnate Immunity

Responding to DNA

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Science Signaling  11 Mar 2008:
Vol. 1, Issue 10, pp. ec88
DOI: 10.1126/stke.110ec88

The body has multiple mechanisms to mount a response to infection, including pathways activated by lipids, proteins, and nucleic acids. However, the mechanism by which DNA viruses trigger an innate immune response that is independent from pathways that involve the Toll-like receptors (TLRs) has been unclear. Muruve et al. found that adenovirus-infected cultured cells stimulated the processing and release of the proinflammatory mediator interleukin-1β (IL-1β) and that this response required the DNA from the virus (delivered by cationic liposomes), but not the capsid, and was independent of TLR signaling. Transfected DNA from bacteria, synthetic DNA, plasmid DNA, or mammalian DNA also triggered IL-1β secretion, although short double-stranded oligonucleotides did not. A minimum size of about 250 base pairs was required to stimulate IL-1β release. IL-1β processing involves the inflammasome, a multiprotein complex that includes a NALP protein (a Nod-like cytosolic receptor), the adaptor protein ASC, and caspase-1. Macrophages from NALP3- or ASC-deficient mice failed to stimulate IL-1β processing and secretion in response to adenovirus infection. However, if the DNA was introduced by cationic liposome delivery, then NALP3 was not required, but ASC and caspase-1 were required, suggesting that DNA delivered by that mechanism may use an inflammasome complex with a different sensor protein. K+ efflux is known to be involved in inflammasome activation, and blocking K+ efflux pharmacologically prevented IL-1β release by adenovirus infection or DNA transfection. Mice deficient in NALP3, ASC, or caspase-1 exhibited a reduced innate immune response to infection with adenovirus. The identification of this new DNA sensor pathway for innate immunity has implications not only for understanding and potentially manipulating the response to pathogen infection but also in autoimmune disease, which may also involve aberrant activity of the inflammasome.

D. A. Muruve, V. Pétrilli, A. K. Zaiss, L. R. White, S. A. Clark, P. J. Ross, R. J. Parks, J. Tschopp, The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103-107 (2008). [PubMed]

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