**Abstract**

Traumatic brain injury (TBI) represents a leading contributor to long-term neurological damage. Though TBI is a leading cause of death and neurological damage worldwide, there exists no therapeutic treatments to alleviate deleterious secondary injury due to neuroinflammation. The continuum of pro- and anti-inflammatory response elicited by TBI is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain poorly defined. This chapter explores rodent models of injury used to study the disease pathology of TBI, as well as the major contributions of the peripheral immune response following injury. Further, this chapter discusses the influence of individual immune cell types on neuroinflammation following TBI, focusing on peripheral monocyte/macrophages, their polarization state, and the current literature surrounding their behavior within the TBI milieu. Finally, cell-to-cell contact regulators that effect peripheral-induced neuroinflammation and may serve as novel targets for therapeutics will be highlighted.

**Keywords:** inflammation, monocytes, traumatic brain injury, blood-brain barrier

## **1. Introduction**

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States and worldwide [1–4]. TBI results from an injury to the brain following exposure to external physical forces including falls, car accidents, explosive blasts, and assault [5, 6]. These injuries often have long-term consequences to the health of injured individuals, and few effective treatments are currently available [6]. The pathophysiology is characterized by damage to the neuronal and glial cells of the brain as well as the associated vasculature [6], and the role of inflammation as a causative agent of tissue injury has emerged as a focus of TBI research [7]. Preclinical research focusing on the mechanisms underlying secondary inflammation and treatment of TBI employs various animal models [8]. This review will discuss TBI as a public health problem, the pathology of TBI and the significance of the peripheral immune response in the outcome of TBI in human and animal models.

### **2. Prevalence of TBI**

Traumatic brain injury is a major cause of death and disability in the United States and worldwide [1–4]. An estimated 69 million people sustain a TBI each year around the world [9]. In the United States, incidence of TBI has risen steadily over recent years. An average of 1.7 million TBIs occurred per year from 2002 to 2006 [1], but an estimated 2.8 million TBIs occurred in 2013 [4]. There is a gender disparity in groups most affected by TBI—in the United States, males are more commonly affected than females. Age group differences are also evident in TBI prevalence, with young children, young adults, and the elderly most frequently suffering from TBI. The specific age groups that most commonly sustain TBIs are ages 0–4 years, 15–24 years, and 75 years and older [4]. Traumatic brain injuries arise from a variety of causes including traffic accidents, falls, abuse, sports injuries, and traumatic impact with an object [4, 5]. The most prevalent causes of injury vary predictably with patient age. Injuries in younger patients are most commonly associated with sports activities or high-risk behaviors such as distracted driving, while injury in the older population of patients is more frequently associated with falls [5]. These events cause injuries of a range of clinical severities including mild, moderate, and severe TBI. In the clinical setting, these injuries are most frequently classified using the Glasgow Coma Score (GCS) [10]. The GCS assesses overall consciousness of the patient and classifies injury severity based on eye, motor, and verbal responses to stimuli [5, 10]. Scores range from 3 to 15. Higher scores correlate with decreased injury severity—for clinical classification purposes, a GCS range of 13–15 has been used to demarcate mild injury, 9–12 for moderate injury, and 8 or less to indicate severe TBI [5]. Imaging modalities including CT and MRI are also used to further assess the severity of TBI and inform prognosis [10].
