Single-cell transcriptomics of resected human traumatic brain injury tissues reveals acute activation of endogenous retroviruses in oligodendroglia

AbstractTraumatic brain injury (TBI) is a leading cause of persistent functional brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. Here, we used single-nuclei RNA-sequencing to study transcriptomic changes in different cell populations from human brain tissue obtained acutely after severe, life-threatening TBI. We found a unique transcriptional response in several cell types, including the activation of an interferon response in oligodendrocyte precursors and mature oligodendrocytes coupled with the transcriptional activation of MHC-class I and II related genes. Thus, oligodendroglia undergoes a transformation to an immune-like cell state immediately after TBI, indicating an important role for these cells in the initiation of neuroinflammation. Notably, the activation of an interferon response correlated with the expression of endogenous retroviruses in oligodendroglia, linking these ancient viral sequences to neuroinflammation. In summary, this work provides a unique insight into the initiating events of the neuroinflammatory response in TBI, which has new therapeutic implications.