**10.3 Eph signaling in immune cells**

Eph/ephrin signaling contributes to immune cell function. For example, EphA4 expression influences multiple different immune cell types including T cells, B cells, platelets, monocyte/macrophages, and dendritic cells [113–115]. Both CD4<sup>+</sup> and CD8<sup>+</sup> T cells have been shown to express EphA4 [116], and EphA4 expression in CD4<sup>+</sup> T cells has been implicated in T-cell migration [117, 118]. EphA4 is also critical in migration of memory T cells in response to ephrin A1 stimulation [116]. EphA4 expression in monocyte/macrophages effects their polarization status by mediating their pro-inflammatory (M1-like) state [115]. Moreover, ephrin A1 stimulation increased monocyte adhesion in a cell culture model through interaction with EphA4 on endothelial cells [119]. While these studies highlight that Eph/ephrin signaling is important in peripheral-derived immune cells, a significant research gap exists concerning the specific mechanisms involved in bi-direction signaling and its role in the function of peripheral immune cells following TBI.

### **11. Conclusions**

Understanding the role of the peripheral-derived immune response to TBI is an important unmet need in TBI research. TBI is a leading cause of death and disability worldwide, and the secondary phase of injury is a critical target for therapeutics. Infiltration of peripheral immune cells through the compromised blood-brain barrier forms a major component of this phase, which can have both beneficial and deleterious effects. Monocyte/macrophages impact the response to TBI by a variety of mechanisms. These cells can cause tissue damage through pro-inflammatory traits or exert pro-recovery effects through anti-inflammatory traits, and the continuum of M1/2 expression is a growing research focus. Tie2 and cell-to-cell contact signaling is gaining attention for its role in peripheral immune cells, which provides additional opportunity for developing novel therapeutic treatments following TBI.

### **Acknowledgements**

We recognize the Institute for Critical Technology and Science, Virginia Tech (JFA award, MHT; Fellowship support AH), and the Center for Engineered Health, VT. This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, R01NS096281 (MHT).

**31**

**Author details**

Virginia Tech, Blacksburg, VA, USA

\*Address all correspondence to: mtheus@vt.edu

provided the original work is properly cited.

Amanda Hazy, Elizabeth Kowalski, Nathalie Groot and Michelle Theus\*

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Peripheral Immune Response Following Traumatic Brain Injury*

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

### **Conflict of interest**

The authors declare no conflict of interest.

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