**10. Cell-to-cell contact in TBI-induced inflammation**

Many cell-to-cell interactions become key in the regulation of inflammation following TBI. As previously mentioned, one of the most detrimental results of TBI is the breakdown of the BBB. Adhesion molecules contribute to cell-cell and cell-extracellular matrix (ECM) interactions that mediate inflammation by promoting peripheral leukocyte infiltration across the BBB and aggregation to the site of injury. This represents the initiation of the inflammatory response [84]. After tissue injury, circulating immune cells will recognize signals released from injured tissue, will stop on the luminal surface of blood vessels, transmigrate paracellularly across the endothelial layer, and enter the injured milieu [85, 86]. This process is referred to as the leukocyte adhesion cascade, which involves tethering, rolling, activation, firm adhesion, and transmigration. Numerous preclinical models have determined the detrimental role of leukocyte migration and accumulation during neuroinflammation in TBI [39, 87].

#### **10.1 Adhesion molecules involved in TBI-induced inflammation**

Adhesion molecules involved in these processes include three major families: selectins, integrins, and immunoglobulins. Selectins are a group of transmembrane glycoproteins expressed on the surface of leukocytes, which express L-selectin, and endothelial cells, which express P- and E-selectins following activation [88]. These glycoproteins mediate the initial tethering of leukocytes to the vessel wall by binding to counter-receptors and rolling within moments of tissue injury [89]. Integrins are a family of adhesion molecules broken into subclassifications of α and β subunits that are responsible for cellular attachment to the ECM and leukocyteendothelial cell adhesion and are denominated by the β subunit CD18. These molecules include CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18, and CD11d/CD18 [90, 91]. Immunoglobulins are a superfamily in which some members are glycoprotein adhesion molecules that regulate the adhesion and migration between leukocytes and endothelial cells during the inflammatory process. These molecules include ICAM-1, ICAM-2, VCAM-1, and PECAM-1 [92]. Key adhesion molecules involved in TBI inflammatory response are summarized in **Table 1**. Eph receptors and their ephrin ligands have also been implicated in the migration step of leukocyte infiltration into injured tissue and subsequent inflammation and will be discussed further.

#### **10.2 Overview of membrane-bound Eph receptors and ephrin ligands**

Eph receptors tyrosine kinases and their membrane-bound ephrin ligands function as mediators of cell migration and a wide-range of cellular functions across different cell types. Eph receptors are the largest family of receptor tyrosine kinases that are activated following cell-to-cell contact [107]. The Eph receptors are classified as either EphA or EphB receptors based on ligand binding. EphB receptors typically bind to transmembrane ephrin B ligands [107–109], while some Eph receptors, such as EphA4, can bind to both A and B ephrins [110]. Eph receptors play critical roles in axon guidance, synaptogenesis, neuromuscular junctions, and vascular remodeling among other roles [107, 109, 111]. Importantly, multiple

**29**

**Adhesion molecule family**

**Molecule**

**Involvement/association with TBI**

Up-regulated 2–24 hrs in percussion model of TBI in rats, activated by IL-1 and TNFα [93].

**Expression** Activated endothelial cells

Slow leukocyte rolling

**Mediates**

Selectin

E-selectin (CD62E, ELAM-1) P-selectin (CD62P)

> Integrins

CD11b CD18/CD11b (Mac-1)

CD18/CD11d [99].

Immunoglobulin

ICAM-1 VCAM-1

**Table 1.**

*Adhesion molecules involved in TBI inflammatory response.*

Increased significantly in TBI up to 72 hours postinjury, and blockade reduced

leukocyte accumulation and improved neurological function following TBI

[100, 101]. Soluble ICAM-1 in CSF was found in patients with severe cerebral

injuries and BBB impairment [102]. Stimulated by IL-8, IL-1, and TNFα.

Significantly decreased in children suffering from inflicted TBI [104].

Activated endothelial

cells [105]

Blockade reduces lesion volume and macrophage infiltration 3 d post-TBI in rats

Increased CSF levels in children with severe TBI and associated with poor outcome [94]. Stimulated by TNFα and IL-1 [95].

Depletion of CD11b macrophages in diphtheria toxin receptor mice increased inflammatory signaling during TBI [96]. This may be due to critical mechanisms for TBI recovery being impaired.

Blockade attenuates neutrophil accumulation following TBI in rats [98].

Neutrophils, monocytes/

Firm adhesion during transmigration of

leukocytes

macrophages, and

NK cells

Neutrophils

Adhesion of leukocytes

and monocyte/

macrophages

Endothelial cells

Leukocyte passage across vascular

endothelial cell layer to injured tissue.

Promotes leukocyte adhesion and

migration [103]

Promotes leukocyte adhesion through

VLA-4 receptor [106]

Secretory granules of platelets and endothelial cells

Leukocyte rolling

Macrophages and microglia

Pathogen and DAMP recognition, phagocytosis, and cell survival [97]

*Peripheral Immune Response Following Traumatic Brain Injury*

*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*

> **Table 1.**

*Adhesion molecules involved in TBI inflammatory response.*

Eph receptors and ephrins play a critical role in inflammation [111]. Ephrin A1 in endothelial cells responds to TNF stimulation, and multiple Eph receptors and ephrins respond to LPS [111]. EphA4 has been demonstrated to influence both spinal cord injury and TBI [111, 112].
