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the subject of much debate. Recently published data suggest that the vagus nerve
is important for immune-to-brain communication. The dorsal vagus complex can
respond to increased levels of local and circulating pro-inflammatory cytokines such
as TNF-. Peripheral stimulation of the
afferent
vagus nerve significantly attenuated
the development of LPS-induced hypotension (shock) in rats exposed to lethal doses
of endotoxin. Experimental activation of the cholinergic anti-inflammatory pathway
by direct electrical stimulation of the
efferent
vagus nerve inhibited the synthesis of
TNF in liver, spleen, and heart, and attenuated serum concentrations of TNF during
endotoxemia. Vagotomy significantly exacerbates TNF responses to inflammatory
stimuli and sensitizes animals to the lethal effects of endotoxin
[35,36]
.
It is not completely clear how the vagus nerve detects low doses of endotoxin or
inflammatory agents, but neurons in the vagus nerve express IL-1 receptor mRNA and
discrete IL-1 binding sites have been identified on glomus cells. Electrophysiological
studies indicate that vagus nerve signals can also be activated by TNF, other cytokines,
mechanoreceptors, chemoreceptors, temperature sensors, and osmolarity sensors. This
presumption allows us to draw an analogy to neurogenic inflammation. However, in
the context of immunological inflammation the cholinergic anti-inflammatory reflex
inhibits inflammation, whereas in neurogenic inflammation the axonal reflex initi-
ates inflammation (
Figure 8.1
). The sensory input from the inflammation site into the
CNS is organized somatotopically, such that information from a discrete peripheral
site is localized precisely in the ascending fiber pathways and brain. Thus, the inflam-
mation-derived sensory input can be processed differentially in the brain, depending
on the location of the inflammatory site and the nature of the sensory signal
[29]
.
The vagus-mediated inflammatory reflex is described as localized, rapid, and
discrete; but it can also induce a systemic anti-inflammatory response if necessary.
This can occur because vagus nerve activity is relayed to the medullary reticular for-
mation, to the locus coeruleus, and to the hypothalamus. Furthermore, sympathetic
nerve fibers can also be affected, leading to an increased release of catecholamines.
Monocytes/macrophages and other immune cells bear functional adrenoreceptors,
and norepinephrine (NE) fulfills criteria for neurotransmission with cells of the
immune system as targets
[37,38]
. Through stimulation of these receptors, locally
released NE, or circulating catecholamines such as epinephrine, affect lymphocyte
traffic, circulation, and proliferation, and modulate cytokine production and the func-
tional activity of different lymphoid cells. In addition, recent evidence suggests that
NE and epinephrine, through stimulation of the 2-adrenoreceptor-cAMP-protein
kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such
as IL-12, TNF-, and INF-, by antigen-presenting cells and T helper (Th) 1 cells,
whereas they stimulate the production of type 2/anti-inflammatory cytokines such as
IL-10 and TGF-. Through this systemic mechanism, endogenous catecholamines
may cause a selective suppression of Th1 responses and cellular immunity, and a Th2
shift toward dominance of humoral immunity. However, in certain local responses,
and under certain conditions, catecholamines may actually boost regional immune
responses, through induction of IL-1, TNF-, and primarily IL-8 production. Thus,
activation of the SNS during an immune response might be aimed at localizing the
inflammatory response, through induction of neutrophil accumulation and stimulation
