**3.1 Neuroinflammation**

Neuroinflammation plays a major role in the secondary phase of injury. While all resident brain cells are involved in some way in the response to TBI, the role of microglia, the resident immune cells of the brain, in neuroinflammation has been particularly well-studied. When brain injury occurs, cells damaged in the primary phase of injury release cell signals known as damage-associated molecular patterns (DAMPs). In the early stages of injury, resident microglial cells are activated by these DAMPs and migrate to the injury site [7, 15]. These cells have a profound effect on both acute and chronic injury processes as they secrete both pro- and antiinflammatory cytokines and can remain activated for up to 18 years after TBI [7, 16]. Cytokines released by microglia have a plethora of effects including alteration of local blood flow and modification of the blood-brain barrier (BBB) [15]. Microglia also assist in walling off the injured area in a protective effort to prevent the spread of bleeding and cellular damage. However, these cells can also generate additional reactive oxygen species (ROS) with damaging effects on cells [17]. While glial cell activation is a key part of the secondary phase of TBI, there is also an important role for the peripheral immune system in TBI recovery. The central nervous system is typically viewed as an immune-privileged site, with few or no peripheral-derived immune cells present. However, following TBI, the blood-brain barrier is damaged, allowing infiltration of peripheral-derived circulating immune cells including neutrophils, macrophages, and lymphocytes [17]. Glutamate excitotoxicity, oxidative stress, and neuroinflammation all contribute to the cellular damage observed in the secondary phase of injury, and the long-term damage resulting from these processes can be extensive. This secondary phase of injury is the primary target for TBI therapeutics—while efforts can be made to reduce TBI incidence, once a TBI has occurred nothing can be done to treat primary injury. Therefore, potential TBI treatments are aimed at reducing damage from the secondary phase of injury [14].
