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

INTRODUCTION Therapeutic effects of acute
neuroinflammation
Prevalence and incidence of stroke and TBI It is important to note that CNS inflammation
Presently, there are over 500 defined neurological is not entirely detrimental. Acute central
disorders caused by trauma, infections, degeneration, inflammation following stroke or TBI is deemed to
autoimmune disorders, structural defects, tumors, or be “neuroprotective”. [3,4] Activated microglia and
strokes of the brain and spinal cord. Of these disorders, CNS-specific T cells, for example, help maintain
[1]
which are characterized by progressive neuronal neurogenesis and spatial learning abilities in the
degeneration and adverse physical and cognitive adult brain. Ziv et al. described how a protective
[8]
[8]
impairments, stroke and traumatic brain injury (TBI) immune response that intends to eliminate danger
both have profound impacts on the American population and minimize tissue (neuronal) loss must be
and worldwide. According to the American Stroke “regulated and shaped by a well-balanced innate-
Association, stroke is the 5th leading cause of death adaptive dialogue” between microglia and systemic
in the United States, killing 130,000 every year, and is T-lymphocytes.
the leading cause of preventable long-term disability.
Healthcare services and medications for stroke alone Acute inflammation in stroke
cost a total of over $34 billion per year nationwide. In the acute inflammatory stage associated with stroke,
[2]
Stroke patients commonly suffer paralysis and other potent pro-inflammatory cytokines TNF-a, interleukin 6
motor dysfunctions, which require extensive therapy. (IL-6), and IL-1β are upregulated in the cerebrospinal
[3]
Similarly, TBI accounted for approximately 2.4 million fluid (CSF) and blood in humans. There is evidence
[9]
emergency department visits, hospitalizations, or that microglia 1 (M1) activated microglia locally
deaths in 2010, and an estimated 5.3 million people are produce TNF-a and IL-1, while IL-6 is also produced
currently living with TBI-related disabilities in the United by neurons. Additionally, Beschorner et al.
[10]
[9]
States. Common features of TBI include bruising, torn demonstrated abundant expression of cluster of
[4]
tissues, bleeding, and physical damage to the brain differentiation 14 (CD14) by ischemia-activated
resulting in long-term complications or death. Among microglia. Since CD14 is key pattern recognition
other effects, characteristic symptoms of mild TBI receptor of the innate immune system also found on
include fatigue or lethargy, a change in sleep patterns, peripheral monocytes involved in cellular activation,
behavioral or mood changes, and trouble with memory, this implicates resident microglial contribution to acute
concentration, attention, or thinking, which are clear ischemic inflammation. Investigations therefore
[10]
clinical manifestations of a neurological disorder. [4] aim to shift classically activated M1 microglia to the
alternatively activated M2 phenotype, which secretes
CNS inflammation in stroke and TBI anti-inflammatory cytokines and neurotrophic factors
The CNS was previously believed to be an immune- that may contribute to neuroregeneration. [6]
privileged site, but a large body of research from
the past few decades reveals a complex interplay Acute inflammation in TBI
between glial cells and systemic leukocytes The TBI brain experiences a short, endogenous pro-
in neuroinflammation. Neuroinflammation is a cell-survival stage in acute neuroinflammation, though
pathological hallmark of many neurological disorders. this is not sufficient for long-term neuroprotection
Following onset of both stroke and TBI, an acute against chronic neuroinflammation. Primary damage
[11]
inflammatory response is mounted to counter initial caused by TBI is mechanical, including neuronal
mechanical damage to brain tissue. Resident microglia injury and disruption of the BBB. Following are two
[11]
become activated and carry out neuroprotective stages of immune response similar to that of stroke:
roles via secretion of pro-inflammatory cytokines. [5,6] an acute “neuroprotective” stage and a chronic
However, infiltration of peripheral leukocytes through “neurodegenerative” stage. Microglial cells become
[6]
the compromised blood-brain barrier (BBB) coupled activated into their pro-inflammatory states, while
[6]
with chronically activated microglia propagates chronic some afford neuroprotective/regenerative capabilities
inflammation and maintains a toxic environment that to combat such damage, but only acutely. Giunta et al.
[6]
[5]
cyclically contributes to secondary axonal death. showed that microglia promoted widespread cellular
[7]
Thus, sequestration of the neuroinflammatory proliferation and focal neurogenesis in the dentate
response has been the target of recent therapeutic gyrus of the hippocampus. However, this protection
investigation to attenuate neurological damage. Our appears to be insufficient as activated microglia
laboratory’s long-understanding neuroinflammation in secreting pro-inflammatory cytokines prove to have a
preclinical models of stroke and TBI is the main theme more powerful role in acute inflammation and beyond;
of this review paper. chronically activated microglia were found in TBI
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ May 17, 2017 83