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

patients up to two decades after the initial traumatic Secondary neuronal damage caused by chronic
insult. [5,11] Neuroinflammation in the TBI brain appears inflammation of activated microglial cells appears
to be more widespread. In TBI mouse model, there to be the link between TBI and Alzheimer’s disease
[5]
was significant upregulation of activated microglial (AD) neuropathology. Several neuropathological
cells in both gray and white matter not only at the TBI hallmarks of Alzheimer’s were observed in brains
impacted cortical site but also at proximal adjacent of chronic TBI patients, namelyamyloid-beta
ipsilateral areas and distal areas. [12] (AB) plaques and neurofibrillary tangles. AB42
[17]
aggregation has been attributed to aging microglia’s
Detrimental effects of chronic reduced phagocytic capacity and therefore decline
neuroinflammation in microglial clearance of AB plaques. Further, post
[5]
Chronic neuroinflammation is mediated by both mortem analysis of TBI patient brains showed senile
central and peripheral sources. [6,13] If this delicate AB plaques present across all age groups, including
innate-adaptive, central-peripheral immune dialogue children, suggesting that TBI is indeed the cause of
between central microglia and systemic lymphocytes AD in these patients. Chronic inflammation and
[5]
is not properly regulated, the resulting regulatory subsequent neuronal degeneration makes patients
[8]
imbalance sustains a harsh environment by chronic vulnerable to neurological deficits. In addition to
neuroinflammation and causes secondary cell death Alzheimer’s disease, TBI is strongly associated with
and adverse neurological deficits. In stroke and TBI, several other neurologic disorders 6 months or more
physical trauma to the BBB activates an innate immune after injury. Uryu et al. characterized multiple
[18]
[19]
response, but the consequences of such mechanical proteins implicated in neurodegenerative diseases in
damage extend beyond if not properly mitigated. post-mortem TBI brains, formed within 4 h to 5 weeks
Peripheral immune cells infiltrate the brain via the of injury. AB plaques co-accumulated with amyloid
compromised BBB and thus exacerbate any existing precursor protein, beta-secretase, and presenilin 1
central neuroinflammation. and the presence of alpha synuclein was confirmed
all within the axonal bulbs. Alpha-synuclein is a
[19]
Stroke and chronic neuroinflammation presynaptic neuronal protein that aggregates to form
The chronic “degenerative” stage of stroke involves toxic protofibrils which are then released from dying
BBB disruption associated with infarction of the neurons to contribute to pathogenesis and also
parenchyma and cerebral vasculature. At this point, accumulated in the CSF following TBI in infants and
[14]
invasion of immune cells and serum proteins through children. [20,21] Synucleinopathy additionally links TBI and
the damaged endothelial cell barrier precipitates Alzheimer’s to Parkinson’s disease (PD). PD displays
adverse physiological consequences such as the same active contribution of reactive microglia to
[4]
propagation of neuroinflammation, increased cerebral loss of dopaminergic neurons. This “reactive gliosis”
pressure and increased cellular death, thus, the initial upregulates pro-inflammatory cytokines in both the
[7]
brain damage caused by stroke is exacerbated by brain and CSF of PD patients. Finally, microglia are
[4]
this secondary BBB destruction. Ischemic stroke was the first to respond to a traumatic spinal cord injury and
found to induce an autoimmune response to neuronal were found to remain activated for at least 6 months
[22]
antigens that can possibly potentiate or ameliorate post-injury in humans. Intraspinal neurons and
long-term neuroinflammation. [15] astrocytes contribute by producing pro-inflammatory
cytokine IL-1B. [22]
TBI and chronic neuroinflammation
Similarly, peripheral immune cells enter the TBI The next section of this paper discusses the sources
brain through the damaged BBB, continuing to of inflammation after TBI and stroke, and how
release pro-inflammatory cytokines, attract more inflammation contributes to the pathogenesis of
immune cells, and activate microglia, rendering these disorders.
a cycle of extended inflammation in the brain. A
decrease in hippocampal neurons and decline in cell SOURCES OF INFLAMMATION: CENTRAL
proliferation in the ipsilateral subventricular zone and AND PERIPHERAL
the subgranular zoneconsistent with TBI pathology
was also observed, indicating the deleterious effects Central and peripheral sources of
of chronic inflammation. Low graft survival of neuroinflammation
[12]
stem cells has been documented in the TBI brain There are both central and peripheral sources
during investigational cell therapy treatments, which contributing to neuroinflammation of neurological
may be attributed to the harsh environment caused disorders [Figure 1]. Traditionally, chronically activated
by this secondary neuroinflammatory response. microglia has been the targets of therapeutic treatment
[16]
84 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ May 17, 2017