LAUSR

Significance Immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, can evoke chronic inflammatory or autoimmune disorders via their activation of innate immune receptors. Since an association of RNA-sensing Toll-like receptor 7 (TLR7) signaling with autoimmunity is well-documented, identification of a DAMP(s) that triggers TLR7 is critical to understanding the disease pathogenesis. By generating the synthetic compound KN69 that inhibits autoimmunity in mouse models, we identified U11 small nuclear RNA (U11snRNA) as a target of KN69 and strong activator of TLR7. We found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and mouse models. Finally, we generated TLR7 agonists and TLR7 antagonists. Our study provides therapeutic insight into autoimmunity and other diseases. The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA’s ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.