Targeted complement inhibition ameliorates the pathological and cognitive outcomes in repetitive mild closed head...

Repeated mild closed head injury (rmCHI) is a significant public health concern, and this type of repetitive injury is garnering increasing attention, not least because of its increasing incidence in sports. The underlying neuroimmune mechanisms secondary to trauma that link rmCHI to cognitive impairment remain to be elucidated, and the contribution of the complement system to the pathological sequelae of this type of brain injury is unexplored. Here, using C57BL/6J mice, we established a repetitive 12-head impact model to investigate the neuroimmune and pathological processes that occur after rmCHI. We specifically studied the role of complement in pathology and cognitive impairment up to 21 days after the cessation of injury in a clinically relevant paradigm using the site-targeted complement inhibitor CR2-Crry. Our analytical methods included mass cytometry, RNA-seq, proteomics, and immunohistological characterization. Mass cytometric analysis revealed that cognitive impairment after rmCHI was associated with major subacute/chronic alterations in local immune cell recruitment, particularly the recruitment and activation of microglia, with marked upregulation of complement receptors and proteins associated with the phagocytic machinery. RNA-seq and proteomic analysis revealed major changes in pathways associated with neurodegeneration, neuronal apoptosis, and the upregulation of complement proteins in animals subjected to rmCHI. Complement inhibition initiated after cessation of injury modulated rmCHI-induced changes and protected against cognitive impairment. In addition to expanding our understanding of the pathological sequelae of rmCHI, these data highlight the therapeutic potential of complement inhibition.