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Marcet et al. The inflamed CNS takes hits centrally and peripherally

and even up to years after initial injury. In animal contribute to the pathogenesis of TBI. [28,59] Leakage
[11]
models it has been shown that microglia can be of chemokines and other inflammatory molecules
active for up to one year after TBI. [6,52-55] Post mortem through the compromised blood brain barrier into
studies have shown activated microglia up to 17 systemic circulation can attract peripheral immune
years after TBI in adult humans. [6,55] The observed cells to the site of injury. This can potentially lead
[28]
cognitive decline, in conjunction with the presence of to an overactive inflammatory response known as
activated microglia after injury suggests a persistent systemic immune response syndrome. Negative
[28]
chronic inflammatory stage mediated by microglia feedback to systemic inflammation is provided by the
that exacerbates TBI and stroke pathology. hypothalamus-pituitary-adrenal axis and sympathetic
nervous system efferents. In TBI, an imbalance
[28]
Peripheral source of neuroinflammation between systemic immune response and negative
The immune system consists of a network of cells, feedback can lead to either excessive organ damage or
tissues, and organs that coordinate to protect susceptibility to infections and lack of regeneration. [28]
the body from foreign pathogens, and promote
tissue healing and regeneration. When the body Role of peripheral chemokines
is injured, cell death leads to leakage of nuclear Cytokines and chemokines are very important to
or cytosolic proteins or protein fragments into the the pathogenesis of TBI. Although their exact role is
extracellular space. These intracellular fragments unclear, data suggests that cytokines play a pivotal role
are pro-inflammatory signals called damage in the body’s response to TBI. After insult to the CNS,
associated molecular patterns (DAMPS). DAMPS upregulation of the following cytokines occurs: TNFa,
are recognized by pattern recognition receptors on IL-1β, IL-2, IL-6, IL-8, IL-4, IL-18. [60-62] One important
dendritic cells, macrophages, and other cells such peripherally secreted chemokine chemokine (C-C
as vascular cells, epithelial cells, and fibroblasts, and motif) ligand 20 (CCL20) is upregulated after TBI,
elicit a pro-inflammatory response from these cells. [56] and interacts with CC chemokine receptor 6 (CCR6)
Once an immune response is mounted, it can either to induce chemotaxis of T cells, B cells, and dendritic
persist as chronic inflammation, or move towards cells. [28] These cells can be found in the spleen,
resolution and tissue healing. and are known to contribute to the pathogenesis of
TBI. [28] Other peripheral cells are found at the site of
Peripheral immune cells are recruited after injury, and contribute to the inflammatory process. It
CNS insult is known that the concentration of neutrophils peaks
The inflammatory response activates the complement around 3-24 h after injury, and the concentration of
system to recruit immune cells to the intrathecal monocytes peaks around 1-2 days after spinal cord
compartment; [48] neutrophils, monocytes and injury. [63]
lymphocytes all cross the blood brain barrier and
chemotax towards the site of injury. Once these Synergistic central and peripheral
[57]
cells have reached the site of injury, they are activated inflammation
to secrete free radicals, pro-inflammatory cytokines, In the case of chronic neuroinflammation, both central
prostaglandins and other inflammatory mediators, and peripheral sources of inflammation work together
resulting in recruitment of more immune cells and to create a hyperactive immune response that
microglia to the site of injury. [57,58] A great deal of ultimately leads to further damage rather than repair
research has been done on microglia, highlighting it of neural tissue. [27,28]
as the key player in coordinating the immune response
after an insult to the CNS. It is well known that CCL20 acts as a chemokine
for CCR6 expressing cells. In an experimental
Systemic immune response autoimmune encephalomyelitis (EAE) model, which
The role of resident immune cells in the CNS after is an animal model for brain inflammation similar
TBI is only part of the story. To get a full picture of to multiple sclerosis in humans, researchers have
the inflammatory response to TBI we must also observed that CCL20 acts as a ligand for CCR6,
look at the peripheral immune system. Multi-organ allowing homing of lymphocytes, and other leukocytes
damage following TBI can lead to a more robust to neural tissue. In this specific case, it allows
[64]
immune response in the brain, highlighting the trafficking of Th17 or Th1 CD4+ Th cells, which
[28]
possibility that systemic inflammation could play release pro-inflammatory cytokines that can cause
a role in neuroinflammation. Because the BBB is chronic inflammation. [64,65] CCL20 expression in the
compromised in a CNS injury, circulating inflammatory choroid plexus allows passage of CCR6+ Th cells to
cells and cytokines can access the brain and enter the CNS in the uninflamed brain, which then
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ May 17, 2017 87