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

Traumatic 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 longterm 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 oligodendrocytes coupled with the transcriptional activation of MHC-class I and class II related genes. Thus, oligodendrocytes undergo 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 immune-related genes correlated with the expression of endogenous retroviruses in oligodendrocytes, 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.