Figure 1.

Model of extracellular DNA induced proinflammatory response. DNaseI digests extracellular DNA that is released from either neutrophils undergoing NETosis or apoptotic/necrotic cells. The undigested DNA may form immune complexes with anti-DNA antibodies, which are then phagocytosed following Fc receptor engagement. DNA can also be phagocytosed in the form of microparticles from apoptotic/necrotic cells. The DNA in the lysosome is degraded by DNase II. Undigested DNA in the lysosome may activate TLR9 to stimulate MyD88. This in turn assembles the Myddosome complex which is composed of MyD88, IRAK1, IRAK2 and IRAK4. TRAF6 is then recruited to the complex, leading to the activation of NF-kb and AP-1. RNA helicase DHX36 and DHX9 were found to identify CpG DNA in certain cell types and trigger MyD88 signalling. TREX1 is localized on the endoplasmic reticulum (ER), digests cytosolic DNA to prevent innate immune response. TREX1 mutations leads to DNA accumulation. This triggers the production of guanosine monophosphate- adenosine monophosphate (cGAMP) by cGAS upon intracellular DNA engagement. cGAMP activates the ER-resident STING, which then is shuttled to ER-Golgi intermediate compartment and the Golgi apparatus. STING initiates TBK1 activation, resulting in the expression of type-I IFNs. Other DNA sensors including double-strand break repair protein MRE11, DNA-dependent protein kinase (DNA-PK), IFNγ-inducible protein 16 (IFI16), protein kinase RNA-activated (PKR), the probable ATP-dependent RNA helicases DDX41 and DDX60, recognize DNA and signal through STING to initiate type-I IFN expression. DNA or RNA is sensed by Leucine-rich repeat flightless interacting protein 2 (LRRFIP2) to activate the β-catenin, resulting in the production of IFN- β. DAI directly recruits TBK1 which leads to type-I IFN production. AIM2 and NLRP3 trigger ASC caspase-1 inflammasome assembly upon dsDNA binding that promote the production of IL-1b and IL-18.