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Immunoregulatory Neuroprotection of Cerebral Ischaemia
Most of the studies on stroke pathophysiology have explored Removal of the spleen before experimental stroke was performed
treatments that interrupt propagation of these cascades in order to by Ajmo et al. to evaluate the role of the peripheral immune
achieve brain tissue protection. Several treatments interfering with system in cerebral ischaemia. Ablation of the largest pool of immune
these pathophysiological cascades have been tested in experimental cells (macrophages, neutrophils, B cells and T cells) due to
stroke and have been shown to be neuroprotective.
However, none splenectomy resulted in smaller infarct size and attenuated
of the neuroprotective approaches tested in clinical trials so far has neuroinflammation after permanent middle cerebral artery occlusion
convincingly demonstrated functional benefits.
Immunohistochemically, brain infiltration by activated
microglia, macrophages and neutrophils was reduced in the
Post-ischaemic Inflammation ischaemic hemispheres of splenectomised rats compared with
and Neurodegeneration controls.
From this experiment a splenic origin of neutrophils
Cell damage progression leading to further neurodegeneration early infiltrating post-ischaemic brain tissues was assumed since blood
after the onset of cerebral ischaemia is mainly attributed to leukocyte counts did not differ between the groups. Even when
Following ischaemic brain injury, early normalised to infarct volume, animals that had been splenectomised
activation of transcription factors (e.g. nuclear factor-κB) is found before showed less neutrophil infiltration and reduced brain tissue
locally in brain cells, leading to an upregulation of pro-inflammatory damage following MCAO.
cytokines and chemokines,
including interleukin-1-beta (IL-1β) and
tumor necrosis factor-alpha (TNF-α). These factors are secreted by To further analyse the role of lymphocytes in post-ischaemic
activated microglial cells, astrocytes,
endothelial cells and inflammation, experimental stroke was performed using severe
as well as by infiltrating mononuclear cells from blood.
combined immunodeficiency (SCID) mice lacking T and B cells.
SCID mice displayed a drastically diminished number of splenocytes,
Recruitment of peripheral immune cells from the blood and spleen to as expected in the absence of T and B cells. MCAO further reduced
the site of brain injury via a compromised blood–brain barrier is the cell number per spleen. However, the number of blood
mediated by different chemotactic factors.
Chemokines also play a mononuclear cells remained unchanged after ischaemia. In
role in mobilisation and attraction of bone marrow-derived stem and comparison with wild-type animals, SCID mice were robustly
precursor cells towards brain lesions.
Due to increased expression of protected from ischaemic injury. Both cortical and total infarct
vascular adhesion molecules on endothelial cells, several immune cell volumes were reduced in SCID mice, suggesting that T and B
types including blood neutrophils (within ~48 hours), monocytes, lymphocytes are harmful players in early ischaemic brain injury.
macrophages (within ~18 hours) and T cells (within ~72 hours) infiltrate However, protection of the ischaemic core was not achieved by the
the brain tissue and exacerbate the ongoing tissue damage.
Subsets absence of T and B cells.
of immune cells attracted to the lesion site, namely activated microglia
and invaded macrophages, have primarily beneficial functions, such as Delayed Peripheral Immunodepression
clearance of debris.
However, cellular release of cytotoxic molecules Cerebral stroke was repeatedly shown to result in post-ischaemic
including inflammatory cytokines (e.g. TNF-α), complement factors and atrophy of the spleen and thymus, as well as in reduced splenic and
free radicals has a destructive effect on tissue.
Systemic immunosuppression within days
after focal stroke has been widely observed and presumably
By contrast, the role of T cells found close to blood vessels in peri- contributes to microbial infections associated with stroke.
infarct areas 24 hours after reperfusion is less clear.
Brain-specific mentioned above, sympathetic nervous system activation due to
T cells, as part of the adaptive arm of the immune system, might brain injury was proposed to lead to rapid and severe functional
attack the brain tissue and exacerbate the damage.
A large increase alteration of the immune system, resulting in a stroke-induced
in splenic T-cell cytokine and chemokine production occurs early after immune depression syndrome (SIDS).
SIDS is manifested by
reperfusion and is suggestive of a role in the adaptive immune reduced T-cell activation and a profound loss of immune T and B
response to stroke.
cells in the blood, spleen and thymus.
Alterations in splenic
function are either due to an increase in splenocytic cell death or
Early Peripheral Immune Activation to a shift in distribution of splenocyte subtypes. Sympathetic
Focal cerebral ischaemia not only produces local inflammatory events signalling to the spleen and thymus stimulates an overabundance
within the ischaemic brain and attracts peripheral immune cells to the of CD4
regulatory T cells, which might inhibit
lesion site, but also exerts long-distance effects on lymphoid organs protective immunity. These so-called ‘master regulators’ of the
by modulating the function of the spleen.
It is unclear how the brain immune system normally limit inflammation and inhibit
communicates a ‘danger signal’ to the spleen. One underlying autoimmune diseases.
mechanism proposed is sympathetic nervous system activation.
Ischaemic brain tissue damage results in the release of pro- In summary, inflammatory mechanisms following stroke result in a
inflammatory cytokines (e.g. TNF-α) and chemokines from biphasic response of the immune system. Initially, rapid activation of
splenocytes in the bloodstream.
splenic T lymphocytes is accompanied by a release of cytokines
within the first hours after stroke, propagating local inflammatory
Within the first 24 hours following cerebral ischaemia, spleen cells processes within the damaged brain. Then, in the subacute phase of
release significant amounts of pro-inflammatory (TNF-α, IFN-γ, IL-6, ischaemia, extended and progressive cell death of splenocytes is
MCP-1 and IL-2) and anti-inflammatory (e.g. IL-10) cytokines. This is induced, leading to massive loss or redistribution of the remaining
followed by extensive movement of leukocytes from the spleen and immune cells.
Such an exhaustion of immunocompetent cells
The leukocytes appear to spread into the blood and invade results in an inability to adequately respond to microbial challenges
the ischaemic penumbra.
due to systemic immunosuppression.
EUROPEAN NEUROLOGICAL REVIEW 43
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