RNA on the outside of cells is no longer a fringe idea. Over the past several years, several groups have shown that RNAs can be modified with N-glycans and displayed on the surfaces of living cells, that surface RNAs help control neutrophil recruitment, and that RNA-binding proteins and glycoRNAs form domains on the membrane that other molecules exploit for entry. What has remained unclear is which specific RNA species sit on which primary immune cells, and whether they do anything functional. Answering that question for rare primary cell populations demanded new tools, and the team developed methods to profile, image and quantify surface RNAs in cells that are available only in limited numbers from patient blood.

Using these approaches, the researchers found that members of the Y RNA family, small noncoding RNAs encoded in the genome and classically bound by the Ro60 autoantigen, preferentially localize to the surface of human monocytes, the circulating precursors of macrophages that stand at the front line of innate immunity. Confocal and super-resolution imaging of live cells, using fluorescent DNA probes complementary to RNY1, RNY3, RNY4 and RNY5 in an intact-surface FISH protocol, showed Y RNA signal colocalizing with plasma membrane markers. Flow cytometry confirmed that monocytes and B cells carry far more surface Y RNA signal than T cells, and transcriptomic comparison of surface-Y-RNA-positive versus negative monocytes revealed that the positive fraction expressed higher levels of membrane protein genes and interleukin and chemokine transcripts.

The clinical hook came from an exploratory pooled cohort of patients with inflammatory bowel disease. The proportion of peripheral monocytes positive for surface Y RNAs was markedly higher in patients with Crohn’s disease or ulcerative colitis than in healthy donors or individuals with irritable bowel syndrome. The separation was strong enough that the surface-Y-RNA-positive monocyte ratio performed well as a diagnostic discriminator, with a receiver operating characteristic area under the curve of 0.924, a cutoff of 0.17, sensitivity of 0.815 and specificity of 0.900. B cells from the same patients also showed elevated frequencies of surface-Y-RNA-positive cells, though the monocyte signal was the more striking separator between inflammatory bowel disease and the non-inflammatory controls.

Correlation is not mechanism, so the team went after what these surface RNAs actually do. A key clue came from extracellular histones, the DNA-packaging proteins that escape from dying cells and circulate as damage-associated molecular patterns. Histones are known to drive lethal inflammation in sepsis and organ injury largely through the Toll-like receptors TLR2 and TLR4, and neutrophil extracellular trap density correlates with histopathological severity in Crohn’s disease. The researchers found that fluorescently labeled histones bound abundantly to monocytes, and that this binding collapsed when surface RNAs were destroyed with RNase A and T1 or removed with a targeted depletion strategy. Strikingly, the same treatments had no effect on histone binding to B cells or other peripheral blood mononuclear cells, pointing to a monocyte-specific, RNA-dependent capture mechanism.

Biochemistry supported a direct interaction. A modified RNA interacting protein capture assay identified histones among the proteins associated with surface Y RNA, and purified assays showed that Y5 RNA binds the H2A-H2B and H3-H4 histone complexes with saturable kinetics, confirmed by gel shift experiments. In other words, Y RNAs appear to act as membrane-tethered adapters that grab extracellular histones and hold them at the monocyte surface, positioning them for recognition by innate immune receptors.

Downstream of that capture, the consequences are inflammatory. When monocytes or THP-1 macrophage-like cells were stimulated with histones, IL6 mRNA and secreted IL-6 protein rose sharply. Silencing RNY1, RNY3, RNY4 or RNY5 with antisense oligonucleotides, degrading surface RNA with RNase A and T1, or blocking TLR signaling with the inhibitor sparstolonin B all blunted that induction, while control oligonucleotides did not. Reporter and signaling assays traced the effect to activation of NF-κB and AP-1, the canonical transcriptional drivers of inflammatory cytokine output. Super-resolution imaging added a spatial dimension: Y RNAs accumulated in the same membrane nanoclusters as TLR4 and TLR2, but not with unrelated membrane proteins such as CD98, TLR5 or TLR10, and preincubating histones with in vitro-transcribed Y RNAs disrupted their colocalization with TLR4, consistent with a competition for binding that maps onto the RNA-histone interface.

The therapeutic implication was tested in the standard dextran sulfate sodium model of colitis. The team developed a depletion strategy, dubbed HASTE, that combines antisense oligonucleotides complementary to Y RNAs with RNase H to eliminate surface Y RNAs without needing to transfect cells. In vitro validation on gel and in human peripheral blood mononuclear cells confirmed that the approach selectively removed surface Y RNA signal while sparing unrelated surface RNAs such as MT-RNR2 and XIST. In mice with DSS-induced colitis, in vivo HASTE efficiently eliminated surface Y RNAs from monocytes, and treated animals showed ameliorated disease activity compared with mice receiving a control antisense oligonucleotide. B cell function appeared largely untouched, since depleting surface Y RNAs did not detectably alter apoptosis or necrosis in anti-IgM-stimulated primary B cells, and the damage-associated molecule HMGB1 still induced IL6 in a Y-RNA-independent manner, suggesting the mechanism is comparatively specific to histone sensing.

The study arrives amid a rapid expansion of interest in cell-surface RNA biology, from the discovery of glycoRNA to reports that surface RNAs form ternary complexes with RNA-binding proteins and heparan sulfate to recruit immune receptors, and that glycoRNA complexed with heparan sulfate regulates VEGF-A signaling. Y RNAs themselves have a long history: they are required for chromosomal DNA replication in human cells, they are the RNA components of Ro60 ribonucleoprotein particles, and Ro60 requires Y3 RNA for cell surface exposure in the cardiac manifestations of neonatal lupus. The new work extends that autoimmunity connection into a mechanistic role in innate immune signaling, and the authors note that histones may also associate nonspecifically with membranes and that additional surface RNAs or cofactors may contribute to histone capture and presentation.

Several caveats temper the enthusiasm. The human cohort was exploratory and pooled, so the diagnostic performance of the surface-Y-RNA-positive monocyte ratio will need validation in larger, independent cohorts before it could inform clinical practice. The mouse experiments rely on a chemically induced colitis model, which recapitulates some but not all features of human inflammatory bowel disease. And the precise molecular architecture of the Y RNA-histone-TLR complex, including which RNA regions contact histones and how the nanoclusters assemble, remains to be resolved. Even so, the study establishes a concrete function for a specific RNA species on the surface of a primary immune cell, offers a plausible mechanistic bridge between cell death, extracellular histones and cytokine storm in the gut, and demonstrates that the amplifier can be silenced. Sequencing data from the human and mouse experiments are publicly available, and the analysis code has been released, giving the field the raw material to test how broadly this surface RNA logic extends across immunity.

Subject of Research: Cell-surface Y RNAs on human monocytes amplify histone-triggered innate immune signaling in inflammatory bowel disease

Article Title: Monocyte surface Y RNAs potentiate innate immunity

Article References: Jiang, X., He, W., Xu, C., Zheng, W., Li, C., Xu, D., Shao, Q., Li, Y., Liu, Z., Li, W., He, S., Wang, Z., Liu, R., Chu, Y., Luo, Z., Huang, X., Liu, J., Yang, E., & Hu, L. (2026). Monocyte surface Y RNAs potentiate innate immunity. Nature Cell Biology. https://doi.org/10.1038/s41556-026-02100-w

Image Credits: AI Generated

DOI: 10.1038/s41556-026-02100-w

Keywords: Y RNAs, monocytes, innate immunity, inflammatory bowel disease, extracellular histones, TLR2, TLR4, NF-κB, IL-6, glycoRNA, colitis, noncoding RNA