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Laboratory of Biomedical Science, North Shore University Hospital, New York University, Manhasset, New York 11030, USA
1Correspondence: Laboratory of Biomedical Science, North Shore University Hospital, New York University, 350 Community Dr., Manhasset, NY 11030, USA. E-mail: kjtracey{at}sprynet.com
ABSTRACT
The central nervous system regulates the innate immune system by elaborating anti-inflammatory hormone cascades in response to bacterial products and immune mediators. We recently discovered that the central nervous system also responds via acetylcholine-mediated efferent signals carried through the vagus nerve. Nicotinic cholinergic receptors expressed on macrophages detect these signals and respond with a dampened cytokine response. Vagus nerve stimulators can mimic this response and can prevent lethal endotoxemia. This newly appreciated cholinergic anti-inflammatory pathway provides a neural substrate to study brain–immune interactions and might be harnessed for therapy of cytokine-mediated disease.—Tracey, K. J., Czura, C. J., Ivanova, S. Mind over immunity.
Key Words: macrophage • TNF-
• HMG-1 • vagus nerve • acetylcholine • placebo effect
WHEN WE SENSE lipopolysaccharide, we are likely to turn on every defense at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area... We live in the midst of explosive devices; we are mined. (Lewis Thomas, 1974)
The innate immune system, specifically macrophages and
neutrophils, is the front line in the defense against invading
pathogens. Invasive stimuli cause these cells to unleash an arsenal of
mediators, including tumor necrosis factor (TNF) and other cytokines.
This response activates coagulation, restricts blood flow to the
affected area, and localizes infection or injury. The overwhelming
majority of mammalian–bacterial interactions result in the eradication
or containment of the pathogens without significant injury to the host.
These ‘successful’ proinflammatory responses are usually kept in
check by the restraining influence of anti-inflammatory mechanisms.
Occasionally, however, the restraining effects of these regulatory
mechanisms fail, and the cytokine cascades become as dangerous as the
pathogens themselves. When this happens, the host can succumb to
complications of systemic inflammation or sepsis. For instance, lethal
endotoxemia initially induces the unchecked systemic overexpression of
TNF and later HMG-1, leading to the death of the host (1
, 2)
. This scenario of cytokine-mediated lethal shock and tissue
injury has been likened to ‘friendly fire’ injury in military
maneuvers.
It is widely known that the central nervous system (CNS) modulates the
fight-or-flight response. For example, the sight of a charging lion
stimulates adrenergic responses that increase cardiac output, mobilize
energy supplies, and support other protective mechanisms necessary for
survival. Recent evidence supports a comparable paradigm for the role
of the CNS in modulating the response to microbial invasion. Cytokines,
endotoxin, and other products of inflammation stimulate afferent neural
signals in the vagus nerve that increase acute-phase responses, induce
fever, and up-regulate the expression of interleukin (IL)-1ß in the
brain (3
4
5)
. Afferent vagus neural signals are rapidly
forwarded to the hypothalamic-pituitary axis, which releases
adrenocorticotropin hormone; the resultant increase in glucocorticoid
levels inhibits cytokine release by the innate immune system
(6)
. Inflammation also activates the CNS to release
melanocyte-stimulating hormone, another potent anti-inflammatory
protein that inhibits cytokine synthesis (7)
. Thus,
afferent neural signals alert the CNS to the presence of microbial
threats or cytokine excess and reflexively stimulate an
anti-inflammatory counter-response to prevent systemic inflammation.
We serendipitously discovered that efferent activity in the vagus nerve
attenuates systemic inflammation (8
, 9)
. Direct electrical
stimulation of the vagus nerve during endotoxemia significantly
attenuates TNF synthesis in tissue macrophages, reduces serum TNF
levels, and prevents the development of lethal hypotension
(8)
. In the absence of electrical stimulation, vagotomy
alone significantly amplifies the TNF response to endotoxemia and
shortens the time to onset of lethal shock. The molecular basis for the
communication between the vagus nerve and the innate immune system is
acetylcholine, the principal neurotransmitter of the parasympathetic
nervous system (8
, 9)
. Macrophages express cholinergic
receptor activity; acetylcholine significantly inhibits LPS-induced TNF
protein release through a post-transcriptional mechanism
(8)
. Acetylcholine significantly inhibits the release of
other proinflammatory cytokines, including IL-1ß, IL-6, and IL-18,
but not IL-10, an anti-inflammatory cytokine. Other cholinergic
agonists (nicotine and muscarine) also inhibit LPS-induced TNF release;
macrophage cholinergic receptor activity is exquisitely sensitive to
-conotoxin, implicating nicotinic-type receptor activity in the
transduction of the cytokine-inhibiting signal. Collectively, these
observations implicate cholinergic signals from the CNS as direct and
rapid modulators of the inflammatory response (8
, 9)
. This
mechanism has been termed the ‘cholinergic anti-inflammatory
pathway.’
It is plausible that vagus nerve stimulators can be developed for therapeutic use in treating inflammation. For instance, it may one day be possible to treat TNF-mediated disease (e.g., rheumatoid arthritis, Crohn’s disease, endotoxemia) with vagus nerve stimulation as a replacement or supplement to anti-TNF strategies. The cholinergic anti-inflammatory pathway may be activated in placebo or acupuncture responses. In such cases there may not be a conscious awareness of the efferent activity in the vagus nerve, but it may be reasonable to train subjects to voluntarily modulate their immune response in a manner fashioned after the voluntary control of heart rate. Perhaps we should not be surprised that the brain possesses the capability to both detect and defuse the minefield of innate immunity.
Received for publication February 14, 2001. Accepted for publication April 2, 2001.
REFERENCES
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