Monocyte surface Y RNAs potentiate innate immunity

RNAs can associate with the surface of diverse cell types, yet the functions of specific RNA species on primary immune cells remain unclear. Here, utilizing methods developed to profile, image and quantify surface RNAs in rare primary cell populations, we found that Y RNAs, a family of small noncoding RNAs, preferentially localize to human monocyte surface. In an exploratory pooled inflammatory bowel disease cohort, the proportion of cell-surface-Y-RNA-positive peripheral monocytes was markedly higher in patients with inflammatory bowel disease than in healthy donors or individuals with irritable bowel syndrome. In vivo depletion of cell-surface Y RNAs ameliorates disease activity in mice with colitis. Mechanistically, cell-surface Y RNAs co-cluster with Toll-like receptors TLR2 and TLR4, bind extracellular histones and promote receptor-mediated histone recognition, thereby activating NF-κB and AP-1 signalling and increasing IL6 expression and IL-6 secretion. These findings identify cell-surface Y RNAs as previously unrecognized amplifiers of inflammatory activation.