**5.1 Blood-brain barrier compromise and immune cell infiltration in TBI**

The blood-brain barrier (BBB) forms a protective layer separating the CNS from the surrounding environment, including circulating peripheral immune cells. The brain is typically regarded as an immune-privileged site due to the operation of the BBB—under normal physiologic conditions, peripheral immune cells in the vasculature cannot enter CNS tissue [7, 15]. The healthy brain exists in a tightly regulated system, and proper operation of the BBB is critical in maintenance of the correct microenvironment for healthy neural function [30]. Multiple cell types including brain endothelial cells, astrocytes, and pericytes compose the BBB [30]. Traumatic brain injury compromises the BBB by direct damage to the cells composing this barrier. The direct damage to cerebral vasculature and disruption of endothelial tight junctions allows entry of immune cells and proteins from the vasculature into cerebral tissue [28, 31]. Rising calcium concentrations activate caspases in endothelial cells, initiating apoptosis of brain endothelial cells and resulting in additional damage to the BBB [28]. The glutamate excitotoxicity observed in TBI also has been shown to increase production of reactive oxygen and nitrogen species (known as oxidative stress), causing further apoptosis of brain endothelial cells [31]. Reactive oxygen species can also increase migration of peripheral monocytes through upregulation of cellular adhesion molecules [31]. The physical damage to brain endothelial and glial cells combined with the activation of apoptotic and stress-related pathways in the endothelium that disrupt tight junctions can increase BBB permeability, allowing circulating peripheral immune cells to enter the brain. Massive influx of peripheral immune cells, induced by brain-derived cytokine release (IL-6, TNF, IL-1β, etc.) at the lesion area over time, further contributes to BBB damage. Additional cytokine, matrix metallopeptidase (MMP), and reactive oxygen species (ROS) released by activated neutrophils and monocyte/macrophages further disrupt the BBB via down-regulation of tight junction proteins as well as through recruitment of additional inflammatory cells [28, 31–34]. An overview of the major peripheral immune cell response is depicted in **Figure 1**.
