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 transfer RNA-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 inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5′-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a 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.

免疫细胞中的细胞应激反应系统在调节炎症性疾病的发展中发挥着至关重要的作用。为了应对细胞损伤或微生物感染，NLRP3 炎症小体的组装会诱导细胞焦亡和炎症细胞因子的释放。同时，血管生成素 (Ang) 介导的转移 RNA 衍生的小 RNA (tsRNA) 可促进细胞在应激条件下的存活。虽然 tsRNA 和炎症小体都是在应激条件下诱导的，但这两个系统之间的相互作用及其在调节炎症性疾病中的影响仍然知之甚少。在这项研究中，证明Ang缺乏加剧了亚砷酸钠诱导的NLRP3炎症小体的激活和细胞焦亡。此外，Ang 诱导的 5'-tsRNA 抑制 NLRP3 炎性体激活和细胞焦亡。从机制上讲，5'-tsRNA 将 DDX3X 蛋白招募到应激颗粒 (SG) 中，从而抑制 DDX3X 与 NLRP3 之间的相互作用，从而抑制 NLRP3 炎症小体的激活。此外，体内结果表明，Ang缺乏导致tsRNA下调，最终导致NLRP3炎症小体依赖性炎症加剧，包括脂多糖诱导的全身炎症和2型糖尿病相关炎症。总而言之，我们的研究揭示了 Ang 诱导的 5'-tsRNA 在通过 SG 调节 NLRP3 炎症小体激活中的作用，并强调 tsRNA 作为治疗 NLRP3 炎症小体相关疾病的有希望的靶点。