Priming the inflammatory pump of the CNS after traumatic brain injury

Abstract

Traumatic brain injury (TBI) can lead to secondary neuropsychiatric problems that develop and persist years after injury. Mounting evidence indicates that neuroinflammatory processes progress after the initial head injury and worsen with time. Microglia contribute to this inflammation by maintaining a primed profile long after the acute effects of the injury have dissipated. This may set the stage for glial dysfunction and hyperactivity to challenges including subsequent head injury, stress, or induction of a peripheral immune response. This review discusses the evidence that microglia become primed following TBI and how this corresponds with vulnerability to a 'second hit' and subsequent neuropsychiatric and neurodegenerative complications.

Keywords: immune challenge; microglia; neuroinflammation; priming; traumatic brain injury.

FIGURE 1. Penetrating and diffuse traumatic brain injuries have varied etiologies and experimental models

Human traumatic brain injuries can either be penetrating/focal or diffuse in nature, with multiple etiologies falling into each of these categories. The animal models used to produce TBIs cause pathology that is in line with these two categories of injury.

FIGURE 2. Microglia are acutely activated following TBI and take on a variety of functional and morphological states

Microglia in their “resting” state are constantly surveying the environment and maintaining homeostasis. Following TBI, microglia are activated by cell debris, neuronal injury, and blood components. Microglia produce the chemokine CCL2, which plays a role in attracting peripheral monocytes to the CNS. Microglia upregulate both M1 and M2 cytokines and surface markers after injury. M1 activation results in production of ROS and RNS and up regulation of pro-inflammatory cytokines and surface markers including IL-1β, TNFα, and CD14. These activated cells can become phagocytic to clear debris. M2 activation is neuroprotective and indicated by upregulation of chitinase and arginase. Rod microglia align with neuronal structures after diffuse injury and are neuroprotective in vitro.

FIGURE 3. Monocytes extravasate and differentiate into brain macrophages

Following injury, circulating monocytes extravasate through activated endothelium and can traffic into the brain parenchyma. These monocytes can differentiate into macrophages. Activated microglia and ramified brain macrophages are nearly indistinguishable by both morphology and cell-surface markers.

FIGURE 4. TBI induces microglial priming and reactivity to immune challenge

Microglia are activated by TBI and respond by producing myriad cytokines and chemokines. This immediate response resolves and some microglia return to homeostasis; however a population of microglia develops a primed or pro-inflammatory profile. This profile is characterized by increased expression of MHCII and CD68. Following secondary insult, illustrated here as a peripheral immune challenge, these primed microglia become hyper-reactive and produce an amplified and prolonged pro-inflammatory response.

FIGURE 5. TBI-induced microglial priming and reactivity to secondary insults has varied consequences

Primed microglia become hyper-reactive following a secondary insult, which can include subsequent TBI, immune challenge, or pre-clinical neurodegenerative disease.