Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks
Abstract
:1. Introduction
2. Overview of TBI
3. Pediatric TBI—Different Than Adults
4. Inflammatory Response to TBI
4.1. Astrocytes
4.2. Microglia
4.3. Pericytes
4.4. Mast Cells
4.5. Peripheral Immune Response to TBI
4.6. Neurogenic Inflammation After TBI
5. Moving Beyond Singular Markers—Taking an Interactive & Dynamic Network Approach to Inflammation
Biological Networks and Relevance to Inflammation after TBI
6. Conclusions and Future Directions for Research and Therapy
Author Contributions
Funding
Conflicts of Interest
References
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Severity | Clinical Criteria | Glasgow Coma Scale (GCS) Score |
---|---|---|
Symptomatic (Possible) | - Blurred Vision - Confusion - Dazed - Dizziness - Focal neurologic symptoms - Headache - Nausea | Mild: 13–15 |
Mild (Probable) | - LOC < 30 min - Post-traumatic anterograde amnesia < 24 h - Depressed, basilar, or linear skull fracture (dura intact) | |
Moderate–Severe (Definite) | - LOC > 30 min - PTA ≥ 24 h - GCS < 13 - One or more of ICH, subdural/epidural hematoma, cerebral contusion, hemorrhagic contusion, penetrating TBI, SAH, brain stem injury | Moderate: 9–12 Severe: 3–8 |
Biological Mechanism | Connection to Inflammation |
---|---|
Excitotoxicity | - As glutamate is known to be a co-stimulator of T cells and a potent gliotransmitter, decreased uptake of glutamate, via downregulation of excitatory amino acid transporters on astrocytes [39] and alterations of GABAergic interneurons [40,41], reduces inhibition of neighbouring excitatory circuits and can activate immune cells (astrocytes, microglia, etc.) |
Mitochondrial Dysfunction & Metabolic Disruption | - Increased Ca2+ influx can overload the mitochondria, promoting network fission [42]. Mitochondrial network fission increases reactive oxygen species (ROS) production, reduces oxidative phosphorylation [43], and has been shown to be required for the activation of microglia in vitro [44] - A shift to glycolysis within neurons is enhanced by cytokines produced by nearby immune cells, notably through activation of the PI3K-mTOR pathway [45]. In combination with mitochondrial dysfunction and increased ROS, this can lead to neuronal degeneration and increase levels of damage-associated molecular patterns (DAMPs) in the surrounding tissue |
Increased Oxidative Stress | - Stabilizes HIF1α [46] and promotes NLRP3 [47] inflammasome formation necessary for the production of inflammatory mediators |
Weakened BBB Integrity | - Increased leakage of DAMPs, including GFAP, NFL, p-tau, and UCH-L1, into the bloodstream and extravasation of peripheral immune cells into the brain [48] |
Cytoskeletal Breakdown/Protein Aggregation | - Increased Ca2+ influx can activate Ca2+-dependent enzymes, such as calpains [49], leading to cytoskeletal breakdown. These broken down proteins can then leak into the peripheral circulation and/or aggregate into plaques within the CNS, leading to further inflammation |
Cerebral Blood Flow Dysregulation | - Hypoxia or ischemia can kill cells, causing them to release their internal contents and activate surrounding immune cells via DAMPs and PRRs - Hypoxia/ischemia can stabilize HIF1α in an ROS-independent manner [50] to increase production of cytokines |
Edema (Vasogenic) | - Facilitated by neurogenic inflammation (release of Substance P and neurokinins) - Increases ability of immune cells to extravasate into the brain - Increases transmission of DAMPs from the brain into the blood to recruit peripheral immune cells |
Edema (Cytotoxic) | - Influx of water into the cell can lead to swelling and membrane and organelle disruption, leading to cell death and release of DAMPs into the extracellular space |
Glial Cell Activation | - Injury to the CNS activates astrocytes and microglia, which reciprocally signal to activate (and de-activate) gliosis. These signals include an initial burst of purinergic substrates, such as ATP from astrocytes, which activate the P2Y12R and P2X4R purinergic receptors [51,52], leading to microglial process extension towards the injury site - Microglia signal to astrocytes to convert them to a neuroprotective phenotype via downregulation of the P2Y1R receptor on the astrocyte surface using TNFα, IL-1β, and IL-6 [53]. The converse can also occur, with microglia inducing a toxic astrocyte phenotype through secreting TNFα, IL-1β, and C1q [54] - CX3CR1 on microglia exhibits a time dependent effect on outcome after injury, playing a key role in inflammation (accumulation of leukocytes [55]), but is required for proper recovery in severe [56] and mild [57] TBI - Formation of a glial scar using Eph/ephrin signaling, namely EphA4 and CSPGs in the CNS [58], can affect vascular permeability and enhance immune cell migration into the injured CNS |
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Fraunberger, E.; Esser, M.J. Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks. Brain Sci. 2019, 9, 319. https://doi.org/10.3390/brainsci9110319
Fraunberger E, Esser MJ. Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks. Brain Sciences. 2019; 9(11):319. https://doi.org/10.3390/brainsci9110319
Chicago/Turabian StyleFraunberger, Erik, and Michael J. Esser. 2019. "Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks" Brain Sciences 9, no. 11: 319. https://doi.org/10.3390/brainsci9110319
APA StyleFraunberger, E., & Esser, M. J. (2019). Neuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks. Brain Sciences, 9(11), 319. https://doi.org/10.3390/brainsci9110319