Effective recognition of double-stranded RNA does not require activation of cellular inflammation

Excess double-stranded RNA (dsRNA) is present in the cytoplasm of human cells, usually following viral infections. Recognition of dsRNAs activates innate immune pathways, leading to cellular inflammation and inhibition of cell growth. Here, we show that an effective dsRNA response may occur without the onset of inflammation. Pro-inflammatory [RLR (retinoic acid-inducible gene I-like receptor)-dependent pathway] and cell growth inhibitory mechanisms [oligoadenylate synthetase (OAS)/ribonuclease L (RNase L)- and dsRNA-activated protein kinase (PKR)-dependent pathways] can act independently. We found that the 5' ends of dsRNA direct the onset of cellular inflammation, whereas the RNA duplex activates the OAS/RNase L and PKR pathways. Unexpectedly, three of the most common human RNA epitranscriptomic marks-i.e., <i>N</i>6-methyladenosine, 5-methylcytosine, and pseudouridine-had almost no influence on the immunogenicity of dsRNA; however, the presence of <i>N</i>6-methyladenosine inhibited the OAS/RNase L pathway. Our observations demonstrate how precisely innate immunity is fine tuned in cells to take appropriate countermeasures when a specific threat arises.