Neuroinflammation in animal models of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Neuroinflammation is prominent in the short and long-term consequences of neuronal injuries that occur after TBI. Neuroinflammation involves the activation of glia, including microglia and astrocytes, to release inflammatory mediators within the brain, and the subsequent recruitment of peripheral immune cells. Various animal models of TBI have been developed that have proved valuable to elucidate the pathophysiology of the disorder and to assess the safety and efficacy of novel therapies prior to clinical trials. These models provide an excellent platform to delineate key injury mechanisms that associate with types of injury (concussion, contusion, and penetration injuries) that occur clinically for the investigation of mild, moderate, and severe forms of TBI. Additionally, TBI modeling in genetically engineered mice, in particular, has aided the identification of key molecules and pathways for putative injury mechanisms, as targets for development of novel therapies for human TBI. This Review details the evidence showing that neuroinflammation, characterized by the activation of microglia and astrocytes and elevated production of inflammatory mediators, is a critical process occurring in various TBI animal models, provides a broad overview of commonly used animal models of TBI, and overviews representative techniques to quantify markers of the brain inflammatory process. A better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI.

Keywords: Astrocytes; Controlled cortical impact; Glia cells; Lateralfluid percussion; Measurements evaluating neuroinflammation; Microglia; Neuroinflammation; Traumatic brain injury (TBI); Weight-drop impact.

Figure 1

After a TBI event, resting glia of multiple types become rapidly activated in a process identified as “reactive gliosis.” This process involves activated microglia initiating and sustaining astrocytic activation via the generation and release of inflammatory markers/mediators (see Tables 1 and 2) that, in turn, act on surrounding glia and neurons via autocrine and paracrine functions (red arrows). Glial activation causes morphological and functional changes within the cells that impact critical neural–glial and glial–glial interactions. This can cause dysfunction of synaptic connections, imbalances of neurotransmitter homeostasis, potential axonal degeneration and neuronal death. Glial cells, most notably astrocytes and microglia, become activated. Their processes become hypertrophied. They upregulate cell surface immune modulatory proteins, and increase the synthesis and release of pro-inflammatory molecules including cytokines, chemokines (see Tables 3 and 4) and prostanoids.