Multiomic analysis identifies involvement of complement-dependent pathways in outcomes after repetitive mild closed head injury

Repetitive mild closed head injury (rmCHI) is a common type of traumatic brain injury and its incidence is increasing, not least due to an increase in the number of sports-related injuries. The underlying neuroimmune mechanisms secondary to trauma that link rmCHI to cognitive decline are not well understood, and the role of complement in this context is largely unexplored. We developed a mouse model of rmCHI and demonstrated complement activation in the brain and cognitive decline, measured 21 days after cessation of injury. These outcomes were accompanied by alterations in local and peripheral immune cell recruitment, together with changes in microglial activation status, as determined by mass cytometry and microscopy. RNAseq and proteomic analysis further revealed major changes in neurodegenerative associated pathways after rmCHI, such as pathways involved neuron development, wound healing and neuronal apoptosis. Complement inhibition initiated after cessation of injury modulated rmCHI-induced changes and protected against cognitive decline.