Small RNA and Toll-like receptor interactions: origins and disease mechanisms

Advances in small RNA sequencing have revealed diverse small noncoding RNAs (sncRNAs) beyond microRNAs (miRNAs), derived from transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and Y RNAs, carrying distinct RNA modifications. These emerging sncRNAs can function beyond RNA interference (RNAi), adopting aptamer-like roles by interacting with Toll-like receptors 7 and 8 (TLR7 and TLR8) via specific sequences, modifications, and structures. We propose a Sequential Activation Hypothesis where initial abnormal sncRNAs - triggered by infections or stresses - activate TLR7/8, leading to autoantibody production against autoantigens like RNA-binding proteins La and Ro. These autoantibody-antigen complexes further promote secondary immunogenic sncRNA production and repetitive TLR7/8 activation, perpetuating a vicious cycle sustaining autoimmunity. TLR7/8's X chromosome location and sex-biased expression contribute to female-dominant autoimmune diseases. Understanding sncRNA-TLR interactions is essential for designing novel therapeutic strategies.