Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome

Abstract The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated tRNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5'-tsRNAs specifically inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5'-tsRNAs recruits DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. In addition, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, which resulted in the amplification of NLRP3 inflammasome-mediated inflammation. This was proved in condition of lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Overall, our study sheds new light on the role of Ang-induced 5'-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.