Role of complement in TBI

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After initial mechanical insult, traumatic brain injury (TBI) is characterized by a dynamic process of secondary injury that involves chronic neuroinflammation and which is implicated in long-term cognitive and motor impairments. It has long been recognized that neuroinflammation is injurious and represents a therapeutic target for treating TBI. The complement system is a central component of the inflammatory cascade, and while there is increasing evidence that complement plays an important role in propagating injury after TBI, complement can also contribute to homeostatic and reparative mechanisms after brain injury. We have shown that transient injury site-targeted complement inhibition is protective against both TBI and stroke through the chronic phase, does not interfere with systemic complement activity, and does not interfere with reparative and regenerative mechanisms. We have also shown continued and high-level complement activation chronically, and this represents a therapeutic target to prevent ongoing inflammation and injury. This proposal builds on these findings. There are three pathways of complement activation, and there is strong experimental and clinical evidence that the lectin pathway plays a key role in activating complement and driving injury after both stroke and TBI, although the role of the lectin pathway in TBI is less well defined. Our first and second aims are to investigate the role of the lectin pathway of complement activation in triggering neuroinflammation and promoting neurodegeneration after TBI. We will accomplish this in a clinically relevant paradigm using a novel targeted inhibitor specific for the lectin pathway. We will use a murine model of moderate to severe controlled cortical impact. The therapeutic rationale for investigating an inhibitor that is specific for only the lectin pathway is that if effective, it will be advantageous to inhibit a single pathway rather than all pathways, since there is less likelihood of disrupting normal immune homeostatic processes and host defense. In aim 3 we will undertake a more detailed mechanistic analysis of how complement drives secondary injury after TBI. Specifically, we will investigate the role of a complement-microglial axis in the neurodegenerative loss of neurons and synapses. Based on our current data, we will investigate the hypothesis that complement- dependent microlgial activation and complement opsonin-directed phagocytosis results in loss of synapses and neurons, which results in impaired cognitive and motor recovery, and that these effects are reversed by complement inhibition.