Monday article #38: Cellular dysfunctioning of astrocytes and its interactions in brain injury
The nervous system (NS), consisting of the central (CNS) and peripheral (PNS) systems, are made up of neurons and glial cells. Glial cells outnumber neurons and do not only carry out a number of developmental and everyday functions, but also have relations to injuries in the nervous system and diseases (Jessen, 2004). Traumatic brain injury (TBI), which can be classified into mild, moderate and severe cases, is defined as the brain alteration caused by an external force or a penetrating object. TBI experienced by a person alters the CNS through a number of mechanisms such as molecular dysfunctioning, oxidative stress and neuroinflammation (Mira et al., 2021).
Astrocytes, along with oligodendrocytes, are the most abundant glial cells found in the CNS, consisting of the brain and spine. Amount of astrocytes are higher compared to oligodendrocytes, and they contain numerous roles including: protecting the brain from external substances circulating in the blood vessels; modify synaptic transmission; remove excess neurotransmitters released from nerve terminals; information processing; controlling potassium levels; and development. Oligodendrocytes are highly specialised cells in the myelin sheath, an insulator surrounding the neuron body that promotes rapid transmission of signals throughout the brain (Jessen, 2004). Other neuroglial cells are microglial cells, which express immune receptors that recognise pathogens and develop its function (Mira et al., 2021). This article would focus on the cellular effects of astrocytes and the interactions between the glial cells upon experiencing TBI.
Astrocytic response is dependent on the severity of the tissue damage caused by TBI (Burda et al., 2016). Neural cell death causes lesions to be formed around the damaged area (Burda et al., 2016), and signalling the release of endothelin B, transcription factor STAT3 and the Wnt signalling regulator Dixdcl lead to the proliferation of astrocytes around the lesion area, thus it would consist of the pre-existing astrocytes and polydendrocytes, formed from the generation of astrocytes during post-TBI (Mira et al., 2016). In addition to proliferation, astrocytes increase in size, which leads to several durable phenotypic sequelae along with epileptiform and neuronal complications in newborns. As a result, astroglial scars form and act as a protective mechanism to prevent spread of damaged tissues to other brain areas. Although astroglial scars have shown regenerative elements, the accumulation could result in undesirable outcomes (Mira et al., 2016).
Figure 1 showed that a decreased expression of glutamate/aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) could contribute to the damaged glutamate buffering, thus releasing an excessive amount of excitatory amino acids from impaired glutamate buffering of astrocytes into the extracellular. As shown in Figure 1, upon experiencing TBI, transcription factors nuclear factor-kB (NF-kB) and N-myc was found to have downregulated GLT-1 expression in mice, accompanied by the reduced expression of potassium channel, thus concluding that TBI causes the uptake of potassium and glutamate to be impaired. Reduction in GLT-1 expression and an increased extracellular glutamate could suggest elements of neuroinflammation (Mira et al., 2016).
Along with causing neuroinflammation, TBI triggers the activation of connexin-43 (Cx43) channels in astrocytes away from the lesion. In addition to acting as a communication platform for the cytoplasm of one cell and another, Cx43 is also a pathway for intracellular and extracellular communication (Mira et al., 2016). Phosphorylation of Cx43 was found to have caused the spread of the damaged brain tissue found away from lesions (Chen et al., 2018), which was suggested to be mediated through ATP signalling (Mira et al., 2016). Astrocytes display innate immune functions through the expression of Toll-like receptor 4 (TLR4), which is triggered after TBI. Astrogliosis, proliferation and hypertrophy of astrocytes, is a contributing factor to brain edema. It was found to have been caused by the increase in mislocalized aquaporin-4 (AQP4). Pathways that lead to edema is to upregulate Na/K/2Ca cotransporter (NKCC) and transient receptor potential melastatin 4 (TRPM4) by activating the NF-kB and an increased astrocytic soma size respectively. Neuroinflammation could be triggered through the translocation of NF-kB which potentially downregulates GLT-1 expression that contributes to excitotoxicity (Mira et al., 2016).
Despite the disruption to the brain, astrocytes also provide protective components to the blood brain barrier through the upregulation of fatty acid-binding protein 7 accompanied by the increase of caveolin-1 in endothelial cells, which prevents neurological deficit, edema and strengthens TBI-induced weak blood brain barrier permeability (Mira et al., 2016).
Traumatic brain injury also affects the oligodendrocytes and microglial cells through various mechanical pathways, making glial responses to TBI dependent on each other as shown in Figure 2. Activities by astrocytes and microglia were observed to have triggered the activity of each other, such that ATP released by astrocytes promotes the activation of microglia, vice versa, thus causing edema and astrogliosis. Although not much is known about the interaction between oligodendrocytes and astrocytes except for the proposed connections to connexin, it is known that the death of oligodendrocytes was caused by the M1 microglia and the release of IL-1β in white matter. Additional astrocytes could have been formed through the proliferation of polydendrocytes at the lesion site (Mira et al., 2016).
To conclude, astrocytic mechanisms have triggered factors contributing to excitotoxicity such as the spread of damage across the brain and a decrease in the glutamate buffering, leading to neuroinflammation, edema and caused disturbance and recuperation of the blood brain barrier permeability. Research focusing on the cellular mechanisms of TBI-induced glial responses aims to identify pharmacological targets to treat TBI patients as means of recovery.
Burda, J.E., Bernstein, A.M. and Sofroniew, M.V. (2016) “Astrocyte roles in Traumatic Brain Injury,” Experimental Neurology, 275, pp. 305–315. Available at: https://doi.org/10.1016/j.expneurol.2015.03.020.
Chen, W. et al. (2018) “Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release,” Journal of Neurophysiology, 119(1), pp. 305–311. Available at: https://doi.org/10.1152/jn.00654.2017.
Jessen, K.R. (2004) “Glial cells,” The International Journal of Biochemistry & Cell Biology, 36(10), pp. 1861–1867. Available at: https://doi.org/10.1016/j.biocel.2004.02.023.
Mira, R.G., Lira, M. and Cerpa, W. (2021) “Traumatic brain injury: Mechanisms of glial response,” Frontiers in Physiology, 12. Available at: https://doi.org/10.3389/fphys.2021.740939.
This article was prepared by Fatini Khadrishah