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Marcet et al. The inflamed CNS takes hits centrally and peripherally
damage from the initial injury, and further research has Immediately after TBI, blood flow to all organs either
suggested that the spleen plays a role in mounting an remained the same or increased for 30 min, then
[76]
immune response to the injured CNS, researchers gradually decreased. Blood flow to the kidney and
tried knocking out the function of the spleen to observe spleen were decreased the most after TBI, which
the effect on TBI and stroke. Ajmo et al. showed that was attributed to sympathetic activity because of the
[73]
removal of the spleen two weeks before permanent high amount of sympathetic vasoconstrictor fibers
MCAO significantly reduced the infarction volume. running to those organs. The resulting hyperactive
[76]
In another study, researchers showed that removal sympathetic response, similar to what happens after
of the spleen just before temporary MCAO caused TBI, is characterized by a widespread vasoconstriction
a reduction in the accumulation of monocytes in that is also selective; flow is decreased through
the brain, but did not significantly change the infarct kidneys and splanchnic organs such as the spleen
size. In addition, splenectomy in rats immediately but not decreased to the heart. It will be interesting
[76]
[68]
after traumatic brain injury reduced circulating levels of if a similar phenomenon characterized by blood flow
pro-inflammatory cytokines, decreased mortality, and alterations in the spleen accompanies stroke.
increased cognitive functioning. Furthermore, it has
[74]
been shown that splenectomy immediately after mild Brain-spleen inflammatory coupling in CNS
TBI in rats attenuated CCL20 chemokine expression injuries
and neurodegeneration in the brain. [27] Lastly, it has been shown that immune cells in the
spleen respond to cholinergic input. Studies have
The spleen and cognitive deficits shown that there is a correlation between brain
Although splenectomy is probably not advisable in injury and autonomic release of pro-inflammatory
human patients that have received a traumatic brain cytokines from splenic macrophages. In a concept
injury or stroke, these studies highlight the importance known as “brain-spleen inflammatory coupling”,
of the spleen in CNS injury. The splenectomy studies, researchers have hypothesized that the changes in
in conjunction with the studies that show a loss of autonomic input after CNS injury lead to systemic
immune cells from the spleen and the appearance of responses, including a response from the spleen.
the same subset of cells in infarcted brain tissue after In increase in pro-inflammatory cytokines in the
stroke, lead researchers to believe that the spleen is brain after CNS injury stimulates the posterior
bolstering the immune response in CNS injury. This hypothalamus to increase sympathetic tone, leading
data suggests that the spleen plays a role in the to catecholamine release from the adrenal glands
secondary wave of neurodegeneration after TBI and and peripheral vasoconstriction. It has been shown
[71]
stroke, leading to more severe cognitive deficits. that macrophages in the liver respond to adrenergic/
cholinergic input, and thus can respond to changes
Blood flow and microglial cytokines in autonomic tone. [71,73,77] The body responds to CNS
Quantifying blood flow to the spleen after injury is injury by increasing sympathetic tone, and immune
important to understand the role of the spleen as cells in the spleen respond to this adrenergic input
a mediator in the immune process. Several ways by producing large amounts of the pro-inflammatory
of measuring blood flow to the spleen have been cytokines TNF-a and IL-1β. [71,78] It is hypothesized that
described. The control of blood supply to the spleen this systemic inflammatory response to TBI and stroke
involves several aspects. It has been shown that exacerbates TBI pathology.
IL-1 increases splenic blood flow by affecting the
sympathetic vasoconstrictor tonus. In order for the Whereas elevated sympathetic tone increases
spleen to remain perfused, resident macrophages the pro-inflammatory response from the spleen,
must produce IL-1β to counteract noradrenergic increased parasympathetic tone has been shown
vasoconstriction. [75] Sympathetic tone reduces to decrease the pro-inflammatory response from
perfusion, whereas inflammatory mediators such as the spleen. [71] Macrophages in the spleen express
IL-1β increase perfusion. a nicotinic catecholamine receptor a7nAChR which
responds to parasympathetic input by reducing
Blood flow after CNS insult and spleen production of the pro-inflammatory cytokine
Blood flow to the spleen after TBI shows a biphasic TNFa. [71,79] Selectively activating this receptor after
hemodynamic pattern. In a study by Yuan et al., stroke in rats was shown to reduce infarct size
[76]
blood flow measurements were taken at 5 min, 15 min, and improve survival. [80] Other studies have shown
30 min, and 60 min after injury. Fluid percussion brain improved neurological outcomes in animal models
injury produced an immediate systemic hypertension for stroke by either direct or indirect stimulation
followed by hypotension and low cardiac output. of this receptor. [71] This evidence suggests that
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ May 17, 2017 89