Cai Jiangxue, Li Chenxuan, Liu Suyuan, Tan Meiling, Sun Yiran, Sun Xiaoxiao, Yang Miaoxin, He Bin
Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, PR China.
Cell Death Differ. 2024 Aug;31(8):1057-1069. doi: 10.1038/s41418-024-01311-8. Epub 2024 May 13.
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起着关键作用。响应细胞损伤或微生物感染，NLRP3炎性小体的组装诱导细胞焦亡和炎性细胞因子的释放。同时，血管生成素（Ang）介导的转运RNA衍生的小RNA（tsRNAs）在应激条件下促进细胞存活。虽然tsRNAs和炎性小体在应激条件下均被诱导，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意义仍知之甚少。在本研究中，证明了Ang缺乏会加剧亚砷酸钠诱导的NLRP3炎性小体激活和细胞焦亡。此外，Ang诱导的5'-tsRNAs抑制NLRP3炎性小体激活和细胞焦亡。机制上，5'-tsRNAs将DDX3X蛋白募集到应激颗粒（SGs）中，从而抑制DDX3X与NLRP3之间的相互作用，进而导致NLRP3炎性小体激活受到抑制。此外，体内结果表明，Ang缺乏导致tsRNAs下调，最终导致NLRP3炎性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。总之，我们的研究揭示了Ang诱导的5'-tsRNAs通过SGs调节NLRP3炎性小体激活的新作用，并突出了tsRNAs作为治疗NLRP3炎性小体相关疾病的有前景的靶点。
