**5. Peripheral-derived immune cell response to TBI**

The peripheral-derived immune cell response is a key feature of the physiologic response to traumatic brain injury, which can have both positive and negative effects. The central nervous system is typically regarded as an immune-privileged site due to the action of the blood-brain barrier (BBB), which prevents peripheral immune cells from readily entering CNS tissue [7, 15]. However, following TBI, the integrity of the blood-brain barrier is compromised by a variety of mechanisms, allowing infiltration of peripheral-derived immune cells into brain parenchyma [28]. Various immune cells including neutrophils, macrophages, and lymphocytes have been shown to infiltrate the lesion area following injury, releasing cytokines that influence recovery [17]. These peripheral immune cells have a profound effect on injury recovery—impact of these infiltrating cells can be either beneficial or

**19**

*Peripheral Immune Response Following Traumatic Brain Injury*

peripheral immune cell infiltration, with a focus on macrophages.

peripheral immune cell response is depicted in **Figure 1**.

*Neutrophils:* Neutrophils arrive at the lesion area in the early stages of injury these cells migrate to the area of injury and infiltrate damaged brain tissue within the first 24 hours postinjury [33]. These cells are recruited by the release of IL-8, a chemoattractant cytokine known to be generated in the early stage of TBI [35]. Numbers of circulating neutrophils rise significantly in the acute phase of TBI. One study found that neutrophils present following TBI appear to be less susceptible to apoptosis than neutrophils in uninjured patients, which may contribute to the increased numbers observed [36]. In contrast to the few studies implicating a positive role for neutrophils in TBI recovery [33, 37], numerous show deleterious effects. One study, using the CCI model, found that neutrophil depletion improved tissue recovery. Neutrophil-depleted mice in this study showed decreased cell death and tissue loss following TBI [38]. Another study assessed the effects of decreased immune cell infiltration following TBI via administration of anti-intercellular adhesion molecule 1 (ICAM1) antibody in a fluid percussion model of rat TBI. Rats given anti-ICAM1

**5.2 Immune cell-specific contribution to TBI**

**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

deleterious to recovery depending on the specific cells and mechanisms involved. While all of these cell types may affect TBI recovery, macrophages in particular have been a focus of TBI research [29]. This review will discuss the general mechanisms of blood-brain barrier compromise after TBI and survey the effects of

*DOI: http://dx.doi.org/10.5772/intechopen.93597*

### *Peripheral Immune Response Following Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.93597*

deleterious to recovery depending on the specific cells and mechanisms involved. While all of these cell types may affect TBI recovery, macrophages in particular have been a focus of TBI research [29]. This review will discuss the general mechanisms of blood-brain barrier compromise after TBI and survey the effects of peripheral immune cell infiltration, with a focus on macrophages.
