Glia and Microglia Cells

From: Traumatic Brain Injury Rehabilitation, Treatment, and Case Management, Fourth Edition <a href="http://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdfhttp://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdf">http://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdfhttp://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdf</a>

Disabilities frequently persist beyond the first weeks following a TBI. The pathological substrate behind these disabilities is most likely due to both the effects of the initial biomechanical insult, i.e., primary damage, and secondary damage resulting from extracranial and intracranial events.

Pathological mechanisms initiated by TBI continue months after the initial insult and are likely to contribute to longlasting neurodegeneration.28,67–70 Here, we discuss how persistent inflammation can lead to chronic neurodegeneration.

Cerebral inflammation is mediated by microglia Inflammation in the brain is typified by microglial activation and the expression of key inflammatory mediators. Microglia are part of the glial family of non-neuronal cells

that mediate immune responses in the CNS. They are the resident macrophages in the CNS given their capability to engulf particles. Microglia mediate responses to pathogens and/or injury and provide support, synaptic pruning, and immunological activities within the CNS.71Microglia routinely remove live glioma cells when activated.72

Microglia are constantly surveying the environment by interacting with both neurons and glia.73 Thus, their responses are dependent on their surrounding environment. One of these microglial responses is the capability to transform from a resting state to an alert and reactive state. This microglial switch occurs when the concentration of particular molecules increases, the exact nature of which requires further study. This implies that microglial activation is responsive to the level of tissue damage. Accordingly, microglial responses are linked to alterations in BBB permeability. As indicated above, the BBB is comprised of a vascular endothelium and a blood cerebrospinal fluid barrier that control the passage of soluble factors from circulating blood to the brain.74

Given that the BBB helps maintain the necessary environment for proper neuronal circuit function, any perturbations in its permeability are likely to lead to microglial activation. Activated microglia will facilitate increases in markers of inflammation as well as inflammatory mediators, such as histocompatibility complex, CD68, and NADPH oxidase.

When microglia become “activated,” they produce inflammatory cytokines. These are small proteins that allow for

immune response signaling. Microglia also undergo structural changes through cytoskeletal rearrangement, altering the pattern of receptor expression and facilitating cytokine communication between cells and enabling migration toward sites of injury or infection.75

Major proinflammatory cytokines are interleukins (IL), interferon-γ (IFN-γ), and tumor necrosis factor

(TNF). These cytokines interact with microglia via surface receptors and adhesion molecules and will modulate destructive processes, such as microglial phagocytic performance. These destructive processes will, in turn,

lead to the recruitment of more microglia.76 Cytokines also control microglial motility, enabling microglia to

migrate to a site of injury following signals of already activated microglia.

The phagocytic line of defense not only diminishes the menace presented by particular particles, but it can remove dead and damaged neurons that can compromise regional signaling.77 Damaged or stressed cells emit signals that are indicative of their deteriorating state.78 These signals, also known as “eat me” signals, are detected by the surrounding microglia.79 It should be noted that “eat me” signaling can be reversed in stressed but viable neurons.78

When addressing differential states of microglial activation, it is not uncommon to note that terminology

used to describe macrophage activation (M1/M2) has been adopted. Under this terminology, microglia under

an M1 state is associated with a defensive proinflammatory reaction. Thus, inflammatory cytokine production by microglia occurs in M1 activation. In contrast, microglia under an M2 “resting state” is associated with

an anti-inflammatory response leading to homeostasis.80,81 Nevertheless, although microglia is functionally

quiescent during the resting state, it is still monitoring the environment through its receptors.79,82

Following either focal or diffuse TBI, microglial upregulation occurs and can be long lasting.28,70,83 Disruptions in BBB integrity play a critical role in the initial neuroinflammatory response. BBB integrity may be compromised by TBI.84 Permeability of the BBB will allow for increased cytokine infiltration to the brain. In turn, increases in cytokine levels will lead to the induction of other cytokines,85 thus ultimately heightening microglial activation. In addition, when the BBB is leaky, proteins and water will contribute to vasogenic edema that, in turn, exacerbates the cytotoxic edema, i.e., cellular swelling, that may already be taking place. Accordingly, microglial activation is prominent at the more focal injury sites during the acute period.86

Increased immune activity can be observed years after the initial injury. Postmortem studies show chronic microglial upregulation in the corpus callosum and frontal lobes of humans months to years postinjury.28,69,87 This is in accordance with animal studies showing prolonged microglial activity after TBI.68,88 Similarly, lasting increases in microglial activation after TBI have been reported in a human study utilizing positron emission tomography. This study found that activation was most notable in subcortical and cortical regions with apparently undamaged tissue. In contrast, persistent microglial activation was not significantly observed in regions with pronounced tissue damage.30 It is likely that the formation of glial scarring isolating the damaged area could have impeded microglial activation.89

Microglia can also switch into an intermediate alert or primed state after TBI. Microglial inflammation after

TBI has been observed to resolve within 72 hours in mice, although a priming effect of an initial traumatic injury is also evidenced at 1 month postinjury with exaggerated expression of proinflammatory cytokines.83 In an alert or primed state, the threshold to switch to an activated state is lowered, therefore potentially leading to an exaggerated inflammatory response when presented with an immune challenge.90 In this instance, microglia become activated in response to infection in the periphery where they would not normally. This phenomenon has been described in aging and, notably, also after TBI.91,92 Experimental TBI studies have indicated that microglia present a primed state during the postacute period accompanied by an exaggerated expression of proinflammatory cytokines associated with neurodegeneration when presented with an immune challenge. This was observed by increased IL-1β and TNF-α following a lipopolysaccharide challenge.83 Microglial activation response is exaggerated to secondary or subthreshold stimuli. The consequence can be substantial changes in

plasticity, development or worsening of cognitive deficits, and acceleration of neurodegeneration.91 Indeed, amplified microglial responses can negatively affect behavioral processes93 and may contribute to the prevalence of affective and cognitive impairments after TBI.94,95 Accordingly, a secondary immune challenge is known to exacerbate cognitive impairments in those that are already presenting cognitive Microglia 7 decline.96,97 A potential mechanism contributing to the exacerbation of cognitive and affective impairments following an immune challenge after TBI can be the interaction of cytokine infiltration from the periphery with primed

microglial responses found after injury.

Increases in cytokines are associated with sickness

behavior that is manifested as fatigue, decreased appetite,

hyperalgesia (i.e., increased sensitivity to pain), impaired

concentration, depression, and sleep disturbance.98,99

Interestingly, the above symptoms, which are prevalent during infection, are also commonly observed with

depression and TBI. Moreover, cytokines appear to contribute to the occurrence of depression by stimulating the

hypothalamic–pituitary axis100 and affecting the metabolism of monoamines, such as serotonin and norepinephrine.101–103 Accordingly, increases in cytokine production

have been associated with depression.104,105

Neuronal activation of brain regions responsive to stress

is associated with microglial activation. These brain regions

include the amygdala, prefrontal cortex, and regions within the hippocampus.106–110 The association between microglial activation and the abovementioned regions is apparent during periods of chronic stress because microglia mediate neuronal adaptation after stress.111 This is particularly concerning after TBI when a heightening of the stress response has been observed 112 and may interfere with experiencedependent plasticity.113 This is in accordance with the high prevalence of immune dysfunction in those suffering from

mood disorders114,115 and includes those that suffered a TBI.