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Page 220 Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13

synapse onto enteric neurons surrounding the GI tract, which can release acetylcholine [68,69] . Acetylcholine
binds to α-7-nicotinic acetylcholine receptors on macrophages, including microglia, and inhibit the release
[70]
of the pro-inflammatory cytokine TNF-α . Other studies also illustrate the ability of the vagal nerve to
[71]
regulate neuroinflammation by sensing increased peripheral pro-inflammatory cytokines . As a negative
feedback loop, pro-inflammatory cytokine release is prevented if increased levels of inflammation are
[72]
[71]
detected through the acetylcholine-mediated anti-inflammatory signaling system . Wang et al. observed
that electrical stimulation of the vagus nerve can inhibit TNF synthesis in wild-type mice but not in α-7-
nicotinic acetylcholine receptor-deficient mice. Collectively, these results support the critical role of the
vagus nerve in regulating microglia activity and neuroinflammation through CAP signaling.

Studies of vagus nerve stimulation have provided additional evidence for vagus nerve afferent involvement
in neuroimmune modulation. For example, non-invasive vagus nerve stimulation is widely used in the
treatment of drug resistant depression and has been shown to increase levels of norepinephrine [73,74] . The
locus coeruleus is an aminergic brain stem nucleus which represents the main source of norepinephrine in
the brain and plays a critical role as a neurotransmitter and neuroimmune modulator, including regulation
of microglial activity. By activating β-receptors on the cell surface, norepinephrine affects microglia cell
dynamics, which then influence neuronal activity [75,76] . These observations indicate the potential of vagus
nerve stimulation to regulate microglial activity.

Recently, the inflammatory reflex was found to be located where vagus afferent fibers activate vagus efferent
[77]
fibers. Borovikova et al. reported that septic shock was prevented by vagus nerve stimulation of the
distal end of the vagus nerve after injection of LPS. This effect is due to CAP activation and the binding of
acetylcholine to α-7-nicotinic acetylcholine receptors in order to inhibit macrophages from releasing pro-
[72]
inflammatory cytokines such as TNF-α . However, the interaction between the vagus nerve and intestinal
immune system is indirect because the vagus nerve does not directly interact with resident macrophages
[78]
in the gut. Therefore, Rosas-Ballina et al. suggested that the vagus nerve tends to activate the splenic
sympathetic nerve through a vago-sympathetic co-activation of ventricular contractility and heart rate [78,79] .
It is hypothesized that released norepinephrine from the distal end of the spleen can bind to the β2
adrenergic receptor of splenic lymphocytes. Its binding leads to the release of acetylcholine, which in turn
[80]
binds to α-7-nicotinic acetylcholine receptors on splenic macrophages and inhibits the release of TNF-α .
However, this hypothesis is still being debated due to the controversial interaction between the spleen and
[81]
the vagus nerve . Furthermore, some studies demonstrate the spleen receives not only sympathetic inputs
but parasympathetic inputs as well. The sympathetic inputs relay information to the spleen via the arteries
while the parasympathetic inputs transfer signals at the tips of the spleen.

The vagus nerve also plays an important role within the neuroendocrine-immune axis, which can regulate
coordinated neural, behavioral, and endocrine responses with the immune system in order to prevent
chronic neuroinflammation. The vagus nerve recognizes peripheral pro-inflammatory cytokines released
by macrophages, such as IL-1, IL-6, and TNF-α and conveys this information to the neurons within HPA
[82]
pathway in order to decrease peripheral inflammation . Overall, the vagus nerve has anti-inflammatory
properties both through its afferent end (activation of HPA axis) and through its efferent end (activation of
CAP).

THE GUT AND THE ENDOCRINE SYSTEM
In addition to the vagus nerve, intestinal microbiota are able to communicate with the CNS through
hormones secreted by glands within the endocrine system. Steroid hormones take part in many critical
physiological processes in our body, such as survival of stress, injury, metabolism, inflammation, salt
and water balance, immune functions, and development of sexual characteristics. Studies show that gut
microbiota are also able produce and regulate these hormones to affect brain activity, including the state of
microglia and neuroinflammation.