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Review
. 2021 Oct 22:12:740939.
doi: 10.3389/fphys.2021.740939. eCollection 2021.

Traumatic Brain Injury: Mechanisms of Glial Response

Rodrigo G Mira  1 , Matías Lira  1 , Waldo Cerpa  1   2
Affiliations
Review

Traumatic Brain Injury: Mechanisms of Glial Response

Rodrigo G Mira et al. Front Physiol. .

Abstract

Traumatic brain injury (TBI) is a heterogeneous disorder that involves brain damage due to external forces. TBI is the main factor of death and morbidity in young males with a high incidence worldwide. TBI causes central nervous system (CNS) damage under a variety of mechanisms, including synaptic dysfunction, protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Glial cells comprise most cells in CNS, which are mediators in the brain's response to TBI. In the CNS are present astrocytes, microglia, oligodendrocytes, and polydendrocytes (NG2 cells). Astrocytes play critical roles in brain's ion and water homeostasis, energy metabolism, blood-brain barrier, and immune response. In response to TBI, astrocytes change their morphology and protein expression. Microglia are the primary immune cells in the CNS with phagocytic activity. After TBI, microglia also change their morphology and release both pro and anti-inflammatory mediators. Oligodendrocytes are the myelin producers of the CNS, promoting axonal support. TBI causes oligodendrocyte apoptosis, demyelination, and axonal transport disruption. There are also various interactions between these glial cells and neurons in response to TBI that contribute to the pathophysiology of TBI. In this review, we summarize several glial hallmarks relevant for understanding the brain injury and neuronal damage under TBI conditions.

Keywords: astrocytes; glia; microglia; oligodendrocytes; traumatic brain injury.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Astrocytes in response to TBI. After TBI of different severities, astrocytes are activated where they proliferate and increase in size. Astrocyte proliferation and activation lead to the formation of a protective glial scar. Several mechanisms at the molecular level accompanied astrocytic activation. Between them, increase calcium influx into astrocytes, downregulation of glutamate transporter GLT-1, the release of proinflammatory cytokines and TLR4 activation, increase p-Cx43 levels, increase AQP expression, and disruption of the blood-brain barrier that contributes to brain edema. The cartoon was made using SERVIER Medical Art templates smart.servier.com.
FIGURE 2
FIGURE 2
Microglia in response to TBI. After TBI of different severities, microglia are activated where they proliferate, increase in size and complexity. There are reports that microglia polarize into possible phenotypes, M1 and M2. M1 microglia release mainly proinflammatory cytokines and the anti-inflammatory cytokine IL-10. On the other hand, M2 microglia release mainly anti-inflammatory cytokines and the proinflammatory cytokine IL-1β. Microglia also activate the NLRP3-inflammasome protein complex and release extracellular vesicles to spread neuroinflammation. The cartoon was made using SERVIER Medical Art templates smart.servier.com.
FIGURE 3
FIGURE 3
Oligodendrocytes in response to TBI. After TBI of different severities, oligodendrocytes go under the process of programmed cell death or apoptosis. Oligodendrocyte death caused decrease levels of myelin proteins leading to demyelination. There is also microtubule breakdown which translates into axonal transport disruption, axonal swelling, and accumulation of βAPP and Aβ peptides. The cartoon was made using SERVIER Medical Art templates smart.servier.com.
FIGURE 4
FIGURE 4
Glial interaction in TBI. In the TBI context, microglia and astrocytes interact through several pathways, and it is still not clear if these interactions potentiate or cushion tissue damage. ATP release from astrocytes induces microglial recruitment, and activated microglia induce astrogliosis and edema. On the other hand, microglia have been shown to regulate ATP release from astrocytes. M1 microglia phenotype and the release of IL-1β in white matter promote oligodendrocyte cell death. There is still unknown about the interactions between mature oligodendrocytes and astrocytes but connexins might play a role. Polydendrocytes, on the other hand, could proliferate and differentiate into astrocytes at the site of the lesion. The cartoon was made using SERVIER Medical Art templates smart.servier.com.
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