The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.
The innate immune system recognizes nucleic acids during infection and tissue damage. Whereas viral RNA is detected by endosomal toll-like receptors (TLR3, TLR7, TLR8) and cytoplasmic RIG-I and MDA5, endosomal TLR9 and cytoplasmic DAI bind DNA, resulting in the activation of nuclear factor-kappaB and interferon regulatory factor transcription factors. However, viruses also trigger pro-inflammatory responses, which remain poorly defined. Here we show that internalized adenoviral DNA induces maturation of pro-interleukin-1beta in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. Correspondingly, NALP3- and ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles. Inflammasome activation also occurs as a result of transfected cytosolic bacterial, viral and mammalian (host) DNA, but in this case sensing is dependent on ASC but not NALP3. The DNA-sensing pro-inflammatory pathway functions independently of TLRs and interferon regulatory factors. Thus, in addition to viral and bacterial components or danger signals in general, inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening their central role in innate immunity.
Muruve
Daniel A
DA
Department of Medicine, University of Calgary, Alberta T2N 4N1, Canada.
Pétrilli
Virginie
V
Zaiss
Anne K
AK
White
Lindsay R
LR
Clark
Sharon A
SA
Ross
P Joel
PJ
Parks
Robin J
RJ
Tschopp
Jurg
J
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology / Q000502:physiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003600:Cytosol / Q000378:metabolism* / Q000382:microbiology / Q000821:virology*; D004247:DNA / Q000276:immunology*; D004279:DNA, Viral / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000821:virology; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011499:Protein Processing, Post-Translational
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004279:DNA, Viral; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D004247:DNA