Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis

Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23653-23661. doi: 10.1073/pnas.1915326116. Epub 2019 Nov 6.


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.

Keywords: DAMPs; TLR7; U11snRNA; autoimmune diseases; type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alarmins / chemistry
  • Animals
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / immunology
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / immunology
  • Base Sequence
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Immunosuppressive Agents / chemical synthesis
  • Immunosuppressive Agents / pharmacology
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / immunology
  • Membrane Glycoproteins / agonists*
  • Membrane Glycoproteins / deficiency
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Middle Aged
  • RNA / immunology
  • RNA / metabolism
  • RNA, Small Nuclear / immunology*
  • Ribonucleoproteins, Small Nuclear / chemistry
  • Ribonucleoproteins, Small Nuclear / immunology
  • Sequence Analysis, RNA
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / deficiency
  • Young Adult


  • Alarmins
  • Immunosuppressive Agents
  • Membrane Glycoproteins
  • RNA, Small Nuclear
  • Ribonucleoproteins, Small Nuclear
  • TLR7 protein, human
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • U11 small nuclear RNA, mouse
  • U11 small nuclear ribonucleoprotein, human
  • RNA