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Neural Control of
Immune System Function
Peder S Olofsson, MD, PhD
The Feinstein Institute for Medical Research
New York, U.S.A.
Learning objectives
• Neural reflexes regulate homeostasis and
optimize organ function.
• The nervous system can sense inflammation
and respond to cytokines in the periphery.
• Neural reflexes regulate inflammation.
• Therapeutic modulation of nerve signals may
treat clinical disease.
Sir Charles Sherrington
“The conception of a reflex therefore
embraces that of at least three
separable structures,
• an effector organ, e. g. gland
cells or muscle cells;
• a conducting nervous path or
conductor leading to that
organ; and
Stimulus
• an initiating organ or receptor
whence the reaction starts.”
- The integrative action of the
nervous system, 1906
Response
Reflex control of the heart
Health
Inflammation
Cytokines
Sickness
syndrome
Swelling
Loss of function
Non-resolving
inflammation
Rheumatoid arthritis
Atherosclerosis
Inflammatory bowel disease
Neurodegeneration
Multiple sclerosis
Cancer
Pain
Anorexia
Fatigue
Shock
Tissue injury
Fever
Humoral anti-inflammatory
Glucocorticoids
IL-10, TGF-b
Soluble receptors
Neural Circuits
Inflammation
Cytokines
Sickness
syndrome
Fig. 1A.
From Symons et al. Pain 134: 232-237, 2008.
Freely available at
www.ncbi.nlm.nih.gov/pubmed/17850969
Fig. 1.
From Chiu et al. Nature Neurosci 15: 1063-1067, 2012.
Freely available at
www.nature.com/neuro/journal/v15/n8/abs/nn.3144.html
Figs. 5 & 6.
From Pacheco et al. Chapter 6. In: Biochemistry, Genetics and Molecular
Biology “Cell Interaction”.
Freely available at www.intechopen.com/books/cell-interaction/cellsmolecules-and-mechanisms-involved-in-the-neuro-immune-interaction
Vagus Nerve
1900-2000:
General Physiology
Visceral sensory
Bradycardia
Hypotension
Bronchoconstriction
Insulin secretion
Gastrointestinal motility
and secretomotor
Fig. X.
From Marieb EN.
Human Anatomy &
Physiology (5th Ed).
San Francisco, CA:
Benjamin Cummings,
2001.
Freely available at
http://legacy.owensbor
o.kctcs.edu/gcaplan/an
at/notes/api%20notes
%20m%20%20peripher
al%20nerves.htm
Blockade of interleukin-1 induced by
hyperthermia by subdiaphragmatic vagotomy
Fig. 2A.
From Watkins et al. Neurosci Lett 183:27-31, 1995.
Available at
www.sciencedirect.com/science/article/pii/030439409411105R
Hepatic (portal) IL-1 stimulates efferent action
potentials in the splenic nerve
Fig. 4.
From Niijima A. J Auto Nerv Sys 61:287–291, 1996.
Available at www.sciencedirect.com/science/article/pii/S0165183896000987
Vagus nerve stimulation attenuates the systemic
inflammatory response to endotoxin
Fig. 3, a & c.
From Borovikova et al. Nature 405:458-462, 2000.
Available at www.nature.com/nature/journal/v405/n6785/full/405458a0.html
Splenic nerve is required for cholinergic
antiinflammatory pathway control of TNF
in endotoxemia
Fig. 3.
From Rosas-Ballina et al. Proc Nat Acad Sci 105:11008-11013, 2008.
Freely available at www.pnas.org/content/105/31/11008.full.pdf
Vagus Nerve
1900-2000:
General Physiology
Visceral sensory
Bradycardia
Hypotension
Bronchoconstriction
Insulin secretion
Gastrointestinal motility
and secretomotor
Marieb EN. Human
Anatomy & Physiology
(5th Ed). San Francisco,
CA: Benjamin Cummings,
2001.
Freely available at
http://legacy.owensboro.
kctcs.edu/gcaplan/anat/n
otes/api%20notes%20m
%20%20peripheral%20ne
rves.htm
2000- today
Immunology
Visceral Sensory
Cytokines
Motor
Anti-inflammatory
Inhibit TNF, IL-1, HMGB1
Nicotinic acetylcholine receptor α7 subunit
is an essential regulator of inflammation
Fig. 5.
From Wang et al. Nature 421: 38488, 2003.
Freely available at
www.nature.com/nature/journal/v
421/n6921/full/nature01339.html
Fig. 1C.
From Wang et al. Nature 421: 384-88,
2003.
Freely available at
www.nature.com/nature/journal/v421
/n6921/full/nature01339.html
Mapping the Cholinergic Antiinflammatory Pathway
n. vagus
Neurophysiology strategy
Stimulate action potentials to
produce effect
Lesion nerve to ablate the effect
• Borovikova et al., Nature, 2000
• Bernik et al., J Exp Med, 2002
• Wang et al., Nature, 2003
• Huston et al., J Exp Med, 2006
• Rosas-Ballina et al., Proc Natl Acad Sci, 2008
spleen
a7
a7
a7
a7nAChR is required in immune cells
a7nAChR deficient
nervous system
a7nAChR deficient
immune system
Fig. 1, A&B.
From Olofsson et al. Mol Med 18:539-543, 2012.
Freely available at
www.ncbi.nlm.nih.gov/pmc/articles/PMC3356417/
How can the
adrenergic splenic
nerve activate
cholinergic a7nAChR
on splenic
macrophages?
a7
J Physiol. 68(2):97-123, 1929.
Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1402860/
Detection of choline-acetyltransferase
activity in lymphocytes
Table 1.
From Rinner, I and Schauenstein, K. J
Neurosci Res 35: 188-191, 1993.
Available at
onlinelibrary.wiley.com/doi/10.1002/jnr.
490350209/abstract
Fig. 2.
From Felten SY and Olschowka J. J Neurosci Res 18:37-48, 1987.
Available at onlinelibrary.wiley.com/doi/10.1002/jnr.490180108/pdf
Choline acetyltransferase-expressing lymphocytes
are in close proximity of splenic nerve endings
Fig. 3D.
From Rosas-Ballina et al. Science 334(6052):98-101, 2011.
Available at www.sciencemag.org/content/334/6052/101.full.pdf
T cells are required for the integrity
of the inflammatory reflex
Fig. 1, C&D.
From Rosas-Ballina et al. Science 334(6052):98-101, 2011.
Available at www.sciencemag.org/content/334/6052/101.full.pdf
Choline acetyltransferase-expressing T cells are required
for the integrity of the inflammatory reflex
Fig. 4, C&D.
From Rosas-Ballina et al. Science 334(6052):98-101, 2011.
Available at www.sciencemag.org/content/334/6052/101.full.pdf
Fig. 4.
From Andersson U and Tracey KJ. Annu
Rev Immunol 30: 313-335, 2012.
Available at
www.annualreviews.org.proxygw.wrlc.org
/doi/full/10.1146/annurev-immunol020711-075015
Effect of electrical vagus nerve stimulation
in some disease models
Endotoxemia
Hemorrhagic shock
Ischemia-reperfusion
Cecal Ligation and Puncture
Colitis
Artery occlusion shock
Carrageenan-induced inflammation
Hemorrhage
Ventilator-induced lung injury
Burn-induced injury
Post-operative ileus
Human activities/conditions and vagus nerve function
Activity/disease
Vagus nerve function
Aerobic exercise
Meditation
Acupuncture
Biofeedback training
Relaxation
Diet-supplemented fish oil
Sepsis
Acute myocardial infarction
Cardiovascular disease
Rheumatoid arthritis
SLE
IBD
Head trauma
Depression
Obesity
Aging
Increase
Increase
Increase
Increase
Increase
Increase
Depressed function coupled to impaired survival
Depressed function coupled to impaired survival
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
Decrease
A clinical trial of vagus nerve stimulation
for treatment of rheumatoid arthritis
Modified from Fig. 2
Koopman et al. American
College of Rheumatology
Meeting, 2012
Freely available at
www.setpointmedical.com/fi
les/acr%202012%20poster%
20spm005%203mb%20size.pdf
Vagus Nerve Stimulation Reduced CRP and
Disease Score in Human Rheumatoid Arthritis
Mean change in DAS score
over time
Figure from Results.
From Koopman et al.
American College of
Rheumatology Meeting,
2012
Freely available at
www.setpointmedical.com/fi
les/acr%202012%20poster%
20spm005%203mb%20size.pdf
DAS
Disease
Activity
Score
CRP
Figure from Results.
From Koopman et al.
American College of
Rheumatology Meeting,
2012
Freely available at
www.setpointmedical.com/fi
les/acr%202012%20poster%
20spm005%203mb%20size.pdf
Neuronal control of immune function is ancient
Fig. 3a.
From Andersson U and Tracey KJ. Annu
Rev Immunol 30: 313-335, 2012.
Available at
www.annualreviews.org.proxygw.wrlc.org
/doi/full/10.1146/annurev-immunol020711-075015
Based on Fig. 1.
From Tracey KJ. Science 332: 673-674, 2011.
Available at
www.sciencemag.org/content/332/6030/673.full
Sun et al. Science 332:729-732, 2011.
Available at www.sciencemag.org/content/332/6030/729.full
The “inflammatory reflex” is not the only pathway
Macrophage cytokines
B cell antibodies
T cell migration
iNKT cell migration
STROKE
Learning objectives
• Neural reflexes regulate homeostasis and optimize
organ function.
• The nervous system can sense inflammation and
respond to cytokines.
• Neural reflexes regulate inflammation.
• Therapeutic modulation of nerve signals may treat
clinical disease.