Transfer RNA-Derived Fragments and isomiRs Are Novel Components of Chronic TBI-Induced Neuropathology

Neuroinflammation is a secondary injury mechanism that evolves in the brain for months after traumatic brain injury (TBI). We hypothesized that an altered small non-coding RNA (sncRNA) signature plays a key role in modulating post-TBI secondary injury and neuroinflammation. At 3threemonths post-TBI, messenger RNA sequencing (seq) and small RNAseq were performed on samples from the ipsilateral thalamus and perilesional cortex of selected rats with a chronic inflammatory endophenotype, and sham-operated controls. The small RNAseq identified dysregulation of 2 and 19 miRNAs in the thalamus and cortex, respectively. The two candidates from the thalamus and the top ten from the cortex were selected for validation. In the thalamus, miR-146a-5p and miR-155-5p levels were upregulated, and in the cortex, miR-375-3p and miR-211-5p levels were upregulated. Analysis of isomiRs of differentially expressed miRNAs identified 3 ' nucleotide additions that were increased after TBI. Surprisingly, we found fragments originating from 16 and 13 tRNAs in the thalamus and cortex, respectively. We further analyzed two upregulated fragments, 3 ' tRF-IleAAT and 3 ' tRF-LysTTT. Increased expression of the full miR-146a profile, and 3 ' tRF-IleAAT and 3 ' tRF-LysTTT was associated with a worse behavioral outcome in animals with chronic neuroinflammation. Our results highlight the importance of understanding the regulatory roles of as-yet unknown sncRNAs for developing better strategies to treat TBI and neuroinflammation.

Automated summary

Neuroinflammation is a secondary injury mechanism that evolves in the brain for months after traumatic brain injury (TBI). This study found that altered small non-coding RNA (sncRNA) signature, especially dysregulation of miRNAs, plays a key role in modulating post-TBI secondary injury and neuroinflammation. These findings contribute to the development of better strategies for treating TBI and neuroinflammation.