Anti-Inflammatory and Protective Role of tiRNA-Glu-TTC-003 in Pediatric Sepsis Via TREM2/TLR4 Signaling Modulation

Sepsis, a severe infection, often leads to an overwhelming inflammatory response. Transfer RNA (tRNA)-derived small RNAs (tsRNAs), a emerging type of small RNAs, is crucial in various biological activities. Nevertheless, the connection between tsRNAs and sepsis is still unknown. We attempt to uncover the functions that these small RNAs play in sepsis. Our studies in humans, cells, and animal models revealed a significant downregulation of tiRNA-Glu-TTC-003 in the plasma of sepsis patients, in vitro macrophage inflammation models, and in the plasma and tissues of mice subjected to cecal ligation and puncture (CLP). Subsequent experiments revealed that the administration of tiRNA-Glu-TTC-003 agomir augmented the survival rate of CLP mice, mitigated organ damage, and attenuated inflammatory responses. In cellular experiments, we observed that overexpression of tiRNA-Glu-TTC-003 ameliorated the inflammatory state of cells and inhibited the expression of inflammation-related factors in M1 macrophages. Additionally, through target gene prediction and screening, we found that tiRNA-Glu-TTC-003 may interact with triggering receptor expressed on myeloid cells 2 (TREM2) to exert its functions. In THP-1 cells, the application of tiRNA-Glu-TTC-003 mimics resulted in an upregulation of TREM2 at both mRNA and protein levels, alongside a downregulation of Toll-like receptor 4 (TLR4) and its downstream effector, myeloid differentiation factor 88 (MyD88). In conclusion, tiRNA-Glu-TTC-003 demonstrates significant anti-inflammatory and protective effects in CLP mice and macrophage inflammation models. These findings suggest that tiRNA-Glu-TTC-003 may be a major factor in the inflammatory response of sepsis and provide a new idea for future treatment.