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 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.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Funding
This work was supported by the National Natural Science Foundation of China (32072807, 32372965), the National Key Research and Development Program of China (2022YFD1300405), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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JC contributed to conceptualization, investigation, formal analysis, validation, visualization, writing—original draft, review, and editing. CL contributed to investigation, formal analysis and methodology. SL contributed to investigation and formal analysis. MT contributed to investigation and validation. YS contributed to investigation and validation. XS contributed to investigation and validation. MY contributed to investigation and validation. BH contributed to conceptualization, resources, writing—review and editing, supervision, project administration, and funding acquisition.
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Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Agricultural University. All experiments followed the “Guidelines on Ethical Treatment of Experimental Animals” (2006) No. 398 set by the Ministry of Science and Technology, China, and Regulation regarding the Management and Treatment of Experimental Animals” (2008) No. 45 set by the Jiangsu Provincial People’s Government.
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Cai, J., Li, C., Liu, S. et al. Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01311-8
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DOI: https://doi.org/10.1038/s41418-024-01311-8