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Neuroscience Refresher
Course
“IT’S ALL IN YOUR HEAD”
The Brain and the Immune System
François M. Abboud, MD
University of Iowa Carver College of Medicine
Experimental Biology Meeting
Boston Convention Center
Saturday, March 28, 2015
Part I:
The Power of the Autonomic
Nervous System
Part II:
Neuro-Immune Synapse
Neuronal Signals Are Powerful
Regulators of Cardiovascular Disease
Nobel Prize
1938
Nobel Prize
1970
Corneille Heymans
Katz, von Euler, Axelrod
Discovery of the role
played by sinus and
aortic mechanisms in
the regulation of
respiration
Discovery of humoral
transmitters in nerve
terminals and the
mechanisms for their
storage, release and
inactivation
Movie clips of people fainting in different
situations
Fig. 1. From Wallin and Sundlof. J
Aut Nerv Sys 6(3): 287-291, 1982.
Available at
sciencedirect.com/science/article/pii/
0165183882900017
Cardiac Vagal Afferent Reflex
Neurocardiogenic Syncope
Vagal
Afferents
Medullary
Cardiovascular
Centers
Sympathoinhibition
Bradycardia
Sympathetic
Efferents
Autonomic Regulation
Old Concept: Autonomic
regulation is essential for
acute circulatory
adjustment
New Concept: Autonomic
dysregulation induces
pathological processes that
determine cardiovascular
mortality
Fig. 3. From Cohn et al.
New Engl J Med 311(13):
819-823, 1984.
Available at
nejm.org/doi/pdf/10.1056/
NEJM198409273111303
Plasma NE levels positively correlate to
increased mortality in heart failure
Direct Recordings of Sympathetic Nerve
Activity in Patients with Heart Failure
(Dramatic Increases Seen with Severe Failure)
Fig. 2. From Ferguson et al.
J Am Coll Cardiol 16:11251123, 1990.
Freely available at
content.onlinejacc.org/article.
aspx?articleID=1115709
Figs. 1, Left, & 4. From
Leimbach et al.
Circulation 73: 913-919,
1986.
Freely available at
circ.ahajournals.org/cont
ent/73/5/913.full.pdf+html
Baro-stimulation Produces Sustained
Hypotension and Bradycardia
in Conscious Dogs
Fig. 1. From Lohmeier et al.
Hypertension
43(2): 306-311, 2004.
Freely available at
hyper.ahajournals.org/content/
43/2/306.full
Improved Survival in Heart Failure
Figs. 7 & 5. From
Zucker et al.
Hypertension 50: 904910, 2007.
Freely available at
hyper.ahajournals.org/
content/50/5/904.full
Figs. 4 & 5C. From Li et al.
Circulation 109(1): 120-124,
2004.
Freely available at
circ.ahajournals.org/content
/109/1/120/F5.expansion.ht
ml
Autonomic Dysregulation Increases
Cardiovascular Mortality
Increased
Sympathetic
Decreased
Parasympathetic
Poor outcomes in
Cardiovascular
Disease
Can it be
Reversed
in Humans?
Current Clinical Trials
Nerve Stimulation
Vagal Stimulation in Heart Failure
Carotid Sinus Nerve
Stimulation in Hypertension
Baroreflex – Sustained
Hypotension/Bradycardia
Control
1
2
3
Volts
4
Part I:
The Power of the Autonomic
Nervous System
Part II:
Neuro-Immune Synapse
(Fatal Conspiracy in Cardiovascular Disease)
The Neuro-Immune Triangle
in Cardiovascular Disease
Autonomic Dysregulation
Increases Mortality
A
Death
Life
B
Inflammatory/Immune
System Causes
CV Damage
C
Autonomic System is
a Powerful Regulator
of the Immune System
Immune System Contributes
Extensively to Cardiovascular Damage
• Atherosclerosis
– Plaques composed of
foam cells, T-cells,
and dendritic cells
• Heart Failure
– Cytokine “storms”
• Atrial Fibrillation
– Fibrosis  Remodeling
• Stroke
– Macrophage extravasation
peroxiredoxin release
• Hypertension
– Innate and Adaptive
immune responses
Immune System & Hypertension
Control
Hence …….
Experimental
NO THYMUS
+
DOCA/SALT
HTN
+
DOCA/SALT
NO delayed
HTN
NO HTN
Svendsen UG. Acta Pathol Microbiol Scand A 84(6):523-528, 1976.
Available at onlinelibrary.wiley.com/doi/10.1111/j.1699-0463.1976.tb00150.x/pdf
Role of Immune System in
Hypertension
Thymic Transplant in SHR
Fig. 4. From Ba et al. J Immunol 128(3): 12111216, 1982.
Freely available at
jimmunol.org/content/128/3/1211.full.pdf+html
Ang II Hypertension Mediated by T-cells
Figs. 5 & 4B (top 2 and bottom
lines only). From Guzik et al. J Exp
Med 204(10): 2449-2460, 2007.
Freely available at
jem.rupress.org/content/204/10/24
49.full
IL-6 Knockout Prevents Ang-II
Hypertension
Arterial Pressure
Afferent Renal Arteriole
Figs. 1 (top 2 lines) & 3. From
Brands et al. Hypertension 56:879884, 2010.
Freely available at
hyper.ahajournals.org/content/56/5/
879.full.
Ang II Increases Renal JAK2 and
STAT-3 Phosphorylation in WT But
Not in IL-6 KO
JAK2
STAT-3
Fig. 4. From Brands et al.
Hypertension 56: 879-884, 2010.
Freely available at
hyper.ahajournals.org/content/56/5/
879.full.
Figs. 1 & 3. From Ganta et al. Am J Physiol Heart Circ Physiol 289:
H1683-1691, 2005.
Reprinted with permission.
Freely available at ajpheart.physiology.org/content/289/4/H1683
Myocardial Infarction
Accelerates Atherosclerosis
SNS induces release of
Hematopoietic endothelial
stem and progenitor cells
from BM to the spleen
where SCF and
accelerates monocyte
production
Dutta et al. Nature Med 18: 902–910, 2012.
Available at nature.com/nature/journal/vaop/ncurrent/abs/nature11260.html
Migration of HSPC from the
Bone Marrow by Sympathetic
Activity (Post-MI)
Fig. 3. From Swirski FK and Nahrendorf
M. Science 339: 161-166, 2013.
Available at
sciencemag.org/content/339/6116/161.full
Circadian Oscillation in Sympathetic Nerve
Activity Govern Recruitment of HSPCs to
Bone Marrow and Leukocytes to Muscle
Scheiermann et al. Immunity 37: 290-301, 2012.
Freely available at
sciencedirect.com/science/article/pii/S1074761312002920
Tonic Suppressive Vagal Influence
on the Immune System
Fig. 1A. From Karimi
et al. Brain Behav
Immun 24: 316-323,
2010.
Available at
sciencedirect.com/sci
ence/article/pii/S0889
159109004838
Fig. 1. From O’Mahony et al. Am J Physiol Regul Integr
Comp Physiol 297(4): R1118-R1126, 2009.
Reprinted with permission.
Freely available at
ajpregu.physiology.org/content/297/4/R1118
Vagal Nerve Stimulation Attenuates the
LPS-Induced TNF Response and
Endotoxin Shock
Fig. 1. From Tracey KJ.
Nature 420: 853-859,
2002.
Available at
nature.com/nature/journal/
v420/n6917/full/nature013
21.html
Fig. 3. From Borovikova et
al. Nature 405: 458-462,
2000.
Available at
nature.com/nature/journal/
v405/n6785/full/405458a0.
html
“The mind has great influence over the body, and maladies often have their
origin there.” Moliére 1622-1673
Proinflammatory State in 2K1C
Hypertension Is Enhanced in a-7
Nicotinic Receptors KO Mice
IL-6
IL-1b
LVW/BW
TNF-a
Glomerular Sclerosis
Fig. 4, B-F. From Li et al. Hypertension 57:
298-307, 2011.
Freely available at
hyper.ahajournals.org/content/57/2/298.full
a-7 Nicotinic Receptors KO Mice
Proinflammatory State in 2K1C
Hypertension
Fig. 5, A & B, right. From Li et al.
Hypertension 57: 298-307, 2011.
Freely available at
hyper.ahajournals.org/content/57/2/298.full
• Is there an intrinsic abnormality in the
response of innate immune cells from WKY
vs. SHR to known immunological Toll-like
Receptor ligands?
• Do angiotensin and the cholinergic
neurotransmitter nicotine alter the
immunological response of immune cells
from WKY vs. SHR?
Hypothesis: Abnormal Autonomic
Immunomodulation
TLR2, TLR3, TLR4,
TLR5, TLR7/8, & TLR9
Adapted from Fig. 1. From Tracey K. Nature Rev Immunol 9: 418-428. 2009.
Available at nature.com/nri/journal/v9/n6/full/nri2566.html
Methods & Protocols
Cytokine Release from Rat Splenocytes
TLR Ligands
Alone
WKY = Normotensive Rat
SHR = Pre-hypertensive
Rats were 3-6 weeks old
TLR Ligands
WITH
Nicotine
OR Ang II
Supernatants were collected for measurements of TNF-alpha, IL-6, IL-10 by
ELISA. A dose response to each TLR ligand was obtained first.
Cytokine Responses to TLR
Activation
Fig. 1. From Harwani et al.
Circ Res 111: 1190-1194, 2012.
Freely available at
circres.ahajournals.org/content/
111/9/1190.full
IL-6 Release Is Enhanced in SHR
Fig. 2. From Harwani et al.
Circ Res 111: 1190-1194, 2012.
Freely available at
circres.ahajournals.org/content/
111/9/1190.full
Methods and Protocols
In Vivo Experiments
Osmotic pumps containing nicotine or saline were implanted. Infusions were
conducted over 24 hours. At 20 hours, animals received an intraperitoneal injection of
either sterile saline or Clo 97 (a TLR7/8 ligand). At 24 hours, sera was collected and
assayed for cytokines.
IL-6 and IL1b Levels Are
Increased in SHR and
Suppressed in WKY by Nicotine
In Vivo Serum Levels
Fig. 3, E & F. From Harwani et
al.
Circ Res 111: 1190-1194, 2012.
Freely available at
circres.ahajournals.org/content/
111/9/1190.full
Activated Macrophages Increase
With Nicotine in SHR
Fig. 4. From Harwani et al.
Circ Res 111: 1190-1194,
2012.
Freely available at
circres.ahajournals.org/con
tent/111/9/1190.full
Summary
1. The autonomic nervous system exerts a powerful modulatory influence
on the immune system with pro-inflammatory morbid cardiovascular
consequences.
2. Vagus nerve activity provides a protective anti-inflammatory effect
mediated by a7-nicotinic cholinergic receptors.
3. In a genetic model of hypertension (SHR), the anti-inflammatory effect
of nicotine on innate immune cell is reversed to a pro-inflammatory
response prior to the onset of hypertension.
4. An excessively large population of CD161+ splenocytes is present in
SHRs in the neonatal state and increases with age as hypertension
progresses
Conclusion
The innate immune system in genetic
hypertension is abnormally regulated by the
autonomic nervous system to trigger proinflammatory responses to endogenous
antigens. These induce pathologic renal and
vascular changes that initiate and sustain the
hypertensive state.
Acknowledgements
Mark Chapleau
Sal Harwani
Madhu Singh
Yongjun Lu
Mike Czicha
Carol Whiteis
Immunologists: Zuhair Ballas, Kevin Legge,
Nick Zavazava and Fayyaz Sutterwalla
Consultants: David Harrison and Howard Jacob
Core Facilities: Cell Sorting and Gene Transfer Vector
François M. Abboud, MD
University of Iowa Carver College of Medicine
[email protected]
François M. Abboud, MD
Associate Vice President for Research
Edith King Pearson Chair of Cardiovascular Research
Chair Emeritus, Dept. of Internal Medicine (1976-2002)
Founding Director, Francois M. Abboud Cardiovascular
Research Center (1974-2012)
Professor of Internal Medicine - Cardiovascular Medicine
Professor of Molecular Physiology and Biophysics
Learn more at
http://www.medicine.uiowa.edu/dept_primary_apr.aspx?a
ppointment=Internal%20Medicine&id=abboudf
To receive a complete set of unaltered slides, please contact the APS Education Office ([email protected])