Signaling of glycoRNAs to Siglec-11 protects neurons by suppressing NF-κB.

Glycosylated RNAs (glycoRNAs), a class of extracellular glycosylated molecules, emerge as key regulators yet with undefined roles in neuroimmune communication. Through neuron-like and glia-like co-culture models, we identify a neuron's protective mechanism mediated by membrane-associated glycoRNAs. Proinflammatory stimulation markedly enhances glycoRNAs expression on human neuroblastoma (SH-SY5Y) neuronal membranes, with their target depletion disrupting their adhesion and concomitantly attenuating the activity of SH-SY5Y cells. Mechanistic analyses establish that the binding of glycoRNAs on SH-SY5Y cells to sialic acid-binding immunoglobulin-like lectin 11 (Siglec-11) on HMC3 cells activates the canonical Siglec-11 signaling pathway. This signaling cascade suppresses NF-κB-mediated proinflammatory pathways, evidenced by diminished NF-κB activation and reduced secretion of inflammatory mediators (interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)), ultimately promoting SH-SY5Y survival. Our findings establish glycoRNAs as critical mediators of intercellular signaling with therapeutic potential in neuroinflammation.