Page 94 - Read Online

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

the peripherally acting cells of the myeloid lineage: elements, antigen presentation to T lymphocytes,
macrophages and dendritic cells. Resident microglia and production of soluble factors that at sufficient
[32]
are capable of clearing foreign pathogens or mediating concentrations can induce further tissue injury
a local, innate immune response in the brain. and gliosis. [6,35] Pro-inflammatory cytokines, such
Microglia can be observed along a continuum of three as these released after neuronal injury, are strong
idealized phenotypic states: resting, activated non- activators of microglia. [41-43] Once activated, microglia
phagocytic (antigen presenting cell like), and activated produce more pro-inflammatory cytokines such as
phagocytic, depending on their level of activation, IL-1β, which ultimately leads to an extensive chronic
which is dictated by the amount and type of cytokines proinflammatory state in the CNS. [11,44]
in the surrounding microenvironment. [33-35] Microglia
sense the microenvironment, and mount a protective Both TBI and stroke is characterized by an initial insult
immune response after TBI, however the response to the CNS, compromising the blood brain barrier and
[6]
is excessive and prolonged, and ends up leading to causing microglial activation. Prolonged microglial
further degeneration instead of regeneration and activation leads to a chronic inflammatory response that
repair. Like macrophages, microglia can polarize into causes excitotoxicity, oxidative stress, mitochondrial
[11]
two subcategories, M1 or M2. M1 is predominantly dysfunction, blood brain barrier disruption, and
[6]
pro-inflammatory, and secretes high levels of pro- inflammation. [45-49] Inflammation activates microglia,
inflammatory cytokines like IL-1, IL12, and IFN-γ, and which then release more pro-inflammatory cytokines
low levels of anti inflammatory cytokines like IL-10. such as TNFa and IL-1β which cause upregulation of
[6]
M2 is typically anti-inflammatory, and acts to clear cell adhesion molecules in the surrounding vasculature
debris and promote regeneration. Pro-inflammatory and lead to a further increase in blood brain barrier
[3]
M1 macrophages predominate after CNS injury. [6,11] permeability, and allows systemic involvement in
neuroinflammation. [6,11,44,50]
Central immune cells contribute to diffuse
axonal injury M1 microglia afford neurodegenerative
As mentioned in the previous section, current research effects
As mentioned before, microglia can polarize into
shows that neuroinflammation is a major source of either M1 or M2 when activated. After CNS injury,
secondary cell death after TBI and stroke. [36-38] The both types of microglia are present, but type
major players in neuroinflammation are immune cells, M1 tends to predominate and persist, leading to
microglia, cytokines, and chemokines that altogether neurodegeneration instead of repair. [6,11] The capacity
exacerbate neuronal cell death after initial injury, of the microglia to drive the response to CNS injury
[39]
and lead to a phenomenon known as diffuse axonal towards either further damage or repair exemplifies
injury, which leads to extensive lesions of cerebral its role as a key player in central immunity, and is
white matter over a widespread area, outside of the the reason it has become the target in studying the
initial lesion. [27,40] Insult to the CNS, either TBI or stroke, cognitive decline due to neuroinflammation after
generates a neuroprotective immune response to traumatic brain injury and stroke.
prevent infection and stimulate neuronal repair. After
injury to the CNS, neurons, astrocytes, and microglial Pathological processes involving microglia
cells all respond to play a role in the inflammatory In addition to recruiting other immune cells to the site
response that ensues. Glutamate release after TBI of injury, microglia contributes directly to neuronal
[27]
causes hyperactivity of neurons, leading to prolonged damage through several pathological processes.
levels of intracellular calcium, and eventually cell When highly activated, microglia are capable of
death, this is known as excitotoxicity. Both astrocytes phagocytosis. In the case of CNS damage, activated
[28]
[35]
and microglia contribute to the inflammatory response microglia phagocytose neuronal elements. Activated
by producing chemokines; chemokines then attract microglia also produce reactive oxygen species and
monocytes to the site of injury. [27] reactive nitrogen species. These are highly reactive
[6]
molecules that increase the oxidative stress, and lead
Microglial cell function and CNS injury to destruction of neuronal cell membranes through
Microglia has several distinctive properties that lipoperoxidation. Cell membranes allow the cell
[51]
allow them to participate in the pathological to maintain homeostasis; once the membrane is
neurodegenerative processes after CNS injury. Upon compromised the cell can die.
activation, microglia undergo morphological changes,
proliferation, and expression of major histocompatibility Chronic activation of microglia
complex (MHC) class II molecules. They are capable The secondary inflammatory damage after insult to
[35]
of phagocytosis of damaged and fragmented neuronal the CNS can be observed as cognitive decline days
86 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ May 17, 2017