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Editorial overview: Immunomodulation: Exploiting the circle between emotions and immunity: impact on pharmacological treatments

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ociety is rapidly changing and so are many aspects of our daily living. From the ways we communicate with each other to the goods we consume, the most striking change we have witnessed in the last decades is the falling of barriers between apparently diverse parts of society and the merging of different cultures and points of view. We have called this phenomenon ‘globalization’ and, according to its definition, this is “the process by which the world is becoming increasingly interconnected as a result of massively increased trade and cultural exchange”. How does globalization manifest in science and scientific research? The short answer is ‘system biology’ e.g. the understanding and analysis of biological phenomena through the lenses of different and yet complementary disciplines (mathematics combined with enzymology for instance)[1]. Translating these concepts into the world of pharmacology and drug discovery, one could say diseases are not just a straight line - one organ/one cell/one signalling pathway - but rather a spider diagram where different ‘factors and problems’ all converge to a single point. With this in mind, it would be tempting to say that the benefits of combining different approaches to achieve an improved and safer pharmacological therapy should be a no brainer. In this section of Immunomodulation, we have been inspired by this concept and have explored the link between mind and body in general - the interconnectedness between emotional states and the immune system specifically - as a possible venue for an improved treatment of both immune and emotional disorders. I have named this area of research Affective Immunology (http://www.affectiveimmunology.com).
Content may be subject to copyright.
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments
Fulvio
D’Acquisto
Current
Opinion
in
Pharmacology
2016,
29:xxyy
http://dx.doi.org/10.1016/j.coph.2016.07.008
1471-4892/Crown
Copyright
#
2016
Published
by
Elsevier
Ltd.
All
rights
reserved.
Society
is
rapidly
changing
and
so
are
many
aspects
of
our
daily
living.
From
the
ways
we
communicate
with
each
other
to
the
goods
we
consume,
the
most
striking
change
we
have
witnessed
in
the
last
decades
is
the
falling
of
barriers
between
apparently
diverse
parts
of
society
and
the
merging
of
different
cultures
and
points
of
view.
We
have
called
this
phenomenon
‘globalization’
and,
according
to
its
definition,
this
is
the
process
by
which
the
world
is
becoming
increasingly
interconnected
as
a
result
of
massively
increased
trade
and
cultural
exchange’.
How
does
globalization
manifest
in
science
and
scientific
research?
The
short
answer
is
‘system
biology’
for
example
the
understanding
and
analysis
of
biological
phenomena
through
the
lenses
of
different
and
yet
complementary
disciplines
(mathematics
combined
with
enzymology
for
instance)
[1].
Translating
these
concepts
into
the
world
of
pharmacology
and
drug
discovery,
one
could
say
diseases
are
not
just
a
straight
line
one
organ/
one
cell/one
signalling
pathway
but
rather
a
spider
diagram
where
dif-
ferent
‘factors
and
problems’
all
converge
to
a
single
point.
With
this
in
mind,
it
would
be
tempting
to
say
that
the
benefits
of
combining
different
approaches
to
achieve
an
improved
and
safer
pharmacological
therapy
should
be
a
no
brainer.
In
this
section
of
Immunomodulation,
we
have
been
inspired
by
this
concept
and
have
explored
the
link
between
mind
and
body
in
general
the
interconnectedness
between
emotional
states
and
the
immune
system
specifically
as
a
possible
venue
for
an
improved
treatment
of
both
immune
and
emotional
disorders.
I
have
named
this
area
of
research
Affective
Immunology
(http://www.affectiveimmunology.com).
Why
would
the
link
between
emotions
and
immunity
be
important
for
drug
design?
And
why
should
pharmacologists,
in
particular,
be
investigating
this
area
of
research?
The
answers
to
these
questions
are
multiple.
First,
some
immunomodulatory
therapies
present
serious
emotional
side
effects
(in-
creased
suicide
idealization)
[2,3],
and
others
might
provide
a
better
thera-
peutic
effect
when
administered
with
‘emotional
modulators’
(see
later)
[4].
Second,
pharmacological
therapies
for
mood
disorders
have
been
shown
to
be
more
effective
when
co-administered
with
immunomodulatory
drugs
in
specific
cohorts
of
patients
[57].
What
are
the
cellular
and
molecular
mechanisms
underlying
the
connection
between
emotions
and
immunity?
We
know
first
of
all
that
the
immune
system
plays
a
key
role
in
maintaining
the
emotional
system
under
check
[810].
Studies
in
both
experimental
animals
and
humans
have
shown
that
a
Fulvio
D’Acquisto
William
Harvey
Research
Institute,
Queen
Mary
University
of
London,
Barts
and
the
London
School
of
Medicine
and
Dentistry,
Queen
Mary
University
of
London,
London,
UK
e-mail:
F.Dacquisto@qmul.ac.uk
Fulvio
D’Acquisto
is
a
professor
of
Immunopharmacology
at
the
William
Harvey
Research
Institute,
Queen
Mary
University
of
London
in
UK.
His
current
field
of
research
(called
Affective
Immunology;
http://www.
affectiveimmunology.com)
investigates
the
cross-talk
between
emotions
and
the
immune
system
as
a
new
venue
for
the
treatment
of
autoimmune
and
inflammatory
disorders.
Available
online
at
www.sciencedirect.com
ScienceDirect
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2016,
29:15
dysfunctional
or
absent
immune
system
causes
some
emotional
disorders
including
anxiety,
depression,
obses-
sive-compulsive
disorders
and
increased
risk
of
suicide
[1113].
In
mice,
the
absence
of
immune
cells
causes
significant
changes
in
memory
and
cognition
[1416]
and
increases
the
animal’s
constitutive
basal
level
of
anxiety-
like
behavior
[17,18].
These
effects
are
linked
to
some
mechanisms
including
the
lack
of
homeostatic
‘patrolling’
exerted
by
the
immune
cells
into
the
CNS
through
newly
discovered
lymphatic
vessels
[19,20].
Studies
also
suggest
that
the
absence
of
T
cells
causes
specific
changes
in
the
gene
expression
profile
of
the
whole
brain,
and
these
have
been
associated
with
both
anxiety
disorders
and
neuro-
degenerative
diseases
[17].
Similar
findings
have
been
reported
in
humans
as
patients
with
either
a
deficient
immune
system
(HIV)
[21,22]
or
those
with
a
hyper
activated
one
(autoimmune
diseases)
are
known
to
pres-
ent
a
high
incidence
of
emotional
disorders
[2326].
Despite
this
evidence,
the
scientific
community
seems
to
be
reluctant
to
appreciate
the
therapeutic
value
of
these
observations.
As
Lasselin
and
colleagues
stated
in
their
article,
most
people
are
still
surprised
to
hear
that
immu-
nity
is
tuned
by
one’s
emotions,
personality
and
social
status’.
Therefore,
it
might
come
not
as
a
surprise
to
know
that
a
defective
immune
response
could
be
treated
by
com-
bined
targeting
of
the
emotional
and
immunological
systems.
As
the
authors
suggested,
this
‘resistance’
might
be
because
emotional
wellbeing
is
not
well-defined
and
hence
difficult
to
quantify.
The
absence
of
‘universal’
and
well-tested
animal
models
for
the
study
of
emotional
wellbeing
might
be
another
cause.
Besides
these
consid-
erations,
I
think
that
the
resistance
also
lays
on
the
fact
that
wellbeing
is
not
just
about
how
we
feel
but
also
about
how
we
are,
as
suggested
by
the
authors
and
others
[27].
This
is
rather
important
as
it
suggests
that
therapies
tackling
‘how
one
is’
or
in
other
terms
one’s
life
style
might
be
potentially
useful
when
combined
with
standard
immunomodulatory
therapies.
Along
these
lines,
a
large
body
of
evidence
has
shown
a
direct
correlation
between
life
style,
oxidative
stress
and
immune
and
inflammatory
chronic
diseases
[2830].
The
article
by
Samina
Salin
discusses
the
role
of
oxidative
stress
in
neuroinflammation
and
the
fact
that
many
psychiatric
illnesses
are
reported
to
exhibit
low
plasma
concentrations
of
a
variety
of
antioxidants
including
glutathione,
vitamin
E
and
coenzyme
Q10.
The
idea
that
the
combined
administration
of
immunomodulators
and
changes
in
life-style
might
be
beneficial
for
the
therapy
of
immune
and
emotional
dis-
orders
is
indeed
fascinating
as
Chiurchiu
and
Maccarone
suggested.
In
their
article,
the
authors
focused
their
atten-
tion
on
bioactive
lipids
[3133]
and
their
dual
role
in
immunity
and
emotions.
From
classical
lipids
like
eicosa-
noids
and
phospholipids
to
more
recent
new
entries
such
as
specialized
pro-resolving
lipid
mediators,
the
range
of
med-
iators
that
could
be
pharmacologically
exploited
for
their
dual
pharmacological
effects
on
emotional
state
[34,35]
and
immunity
[36,37]
seems
to
be
growing
by
the
year.
Of
a
particular
note
for
the
topic
of
this
volume,
the
endocanna-
binoid
anandamide
is
the
prototype
of
lipid
mediator
that
has
remarkable
effects
on
the
immune
system
[38]
and
is
equally
effective
in
emotional
disorders
[39,40]
as
its
name
(which
means
‘inner
bliss’)
seems
to
suggest.
The
idea
of
drugs
with
a
potential
double
role
in
the
immune
and
emotional
systems
is
not
entirely
new.
Neigh
and
Ali
have
provided
an
interesting
overview
of
immunomodulatory
drugs
from
the
classical
steroid
to
the
modern
biologic
against
inflammatory
cytokines
that
are
proven
for
the
treatment
of
post-traumatic
stress
disorders
(PTSD).
The
authors
also
highlighted
that
several
drugs
used
for
the
treatment
of
PTSD,
including
selective
serotonin
re-uptake
inhibitors
(SSRI),
have
been
shown
to
exert
anti-inflammatory
effects
on
T-lymphocytes,
dendritic
cells,
and
neutrophils.
This
simultaneous
effect
on
both
the
immune
and
emo-
tional
system
can
also
be
achieved
by
co-therapy.
In
their
article
Rosenblat
and
co-authors
describe
the
efficacy
of
co-therapy
in
the
treatment
of
patients
suffering
from
bipolar
disorders.
Similar
to
what
has
been
found
for
PTSD
or
depression,
a
wide
range
of
drugs
including
N-
acetylcysteine,
infliximab,
pioglitazone,
celecoxib,
aspirin,
and
omega-3
polyunsaturated
fatty
acids
have
shown
an
antide-
pressant
effect
in
bipolar
disorders
when
administered
adjunc-
tively
to
conventional
treatments.
Co-therapies
have
also
been
particularly
useful
in
the
context
of
immunomodulatory
treatment.
Indeed,
Kovacs
and
co-authors
provided
an
extensive
overview
of
the
side
effects
on
the
emotional
system
of
a
powerful
antiviral
and
anticancer
drug:
interferon-alpha
[41].
As
stated
by
the
authors,
a
staggering
10%40%
of
patients
receiving
this
therapy
develop
a
full
depressive
disorder
syndrome
that
can
include
suicidal
ideation,
aboulia,
lack
of
motiva-
tion,
social
withdrawal,
guilt,
anhedonia,
irritability,
anxiety,
and
crying
[42,43].
Luckily,
the
side
effects
of
this
drug
seem
to
be
tapered
by
the
co-treatment
with
traditional
drugs
such
as
SSRI
[44]
or
novel
ones
such
as
a
diet
rich
in
omega-3
polyunsaturated
fatty
acids
[45].
Is
there
any
other
approach
to
co-therapies?
As
we
have
just
started
to
better
appreciate
the
colloquium
between
the
brain
and
immune
cells,
an
extra
level
of
control
has
been
taking
the
center
stage
in
the
scientific
arena:
the
gutbrain
axis
or
to
be
more
precise
the
gutbrain
immune
system
triangle.
The
colloquium
has
now
been
transformed
into
colloquia.
The
discoveries
emerging
from
this
field
of
research
are
bewildering,
to
say
the
least
[4648].
As
Hayley
and
colleagues
pointed
out,
bacterial
communities
generally
present
in
the
gut
are
sensitive
to
a
variety
of
challenges,
including
stressors
the
stressors
being
of
emotional
nature
(the
most
famous
2
Immunomodulation
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Current
Opinion
in
Pharmacology
2016,
29:15
www.sciencedirect.com
‘gut
feelings’)
or
a
pathogenic
factor
for
the
immune
system.
In
their
view,
the
gut
is
the
real
link
between
the
brain
and
the
immune
system
as
evidenced
by
the
fact
that
the
benefits
of
microbiota-targeting
compounds
on
mood
states
could
be
related
to
their
actions
on
immune
processes.
Prebiotics
and
pro-biotics
are
the
new
classes
of
drugs
currently
under
investigation
for
their
use
in
immune
and
psychiatric
disorders
[4951].
Where
do
we
move
from
here?
Figure
1
shows
a
tag
cloud
analysis
of
the
most
common
terms
present
in
all
the
contributions
to
this
volume
and
highlight
the
’chal-
lenges’
ahead
of
us.
From
my
personal
perspective,
there
are
still
two
most
important
aspects
that
need
to
be
explored.
First,
the
role
of
emotions
and
immune
cells
as
guardian
of
wellbeing.
As
Ruslan
Medzhitov
has
highlighted
in
his
recent
reviews
[52,53],
the
state
of
homoeostasis
of
the
immune
system
cannot
be
just
inter-
preted
as
absence
of
threats
from
the
external
environ-
ment.
Emotions
like
stress
or
simply
having
a
laugh
are
part
of
daily
living,
and
as
Steve
Cole
and
colleagues
has
very
elegantly
shown,
they
directly
steer
the
immune
system
towards
specific
tasks
such
as
antibacterial
de-
fense
pathway
or
antiviral
response
depending
on
social
factors
such
as
isolation
[5456].
Unraveling
the
molecu-
lar
mechanisms
regulating
these
events
might
provide
an
immense
resource
for
pharmacologists
to
identify
new
molecules
and
drugs
that
can
help
maintain
the
host
in
a
state
of
immunological
equilibrium
and
possibly
a
healthy
emotional
state.
The
other
aspect
that
has
not
been
thoroughly
investi-
gated
is
the
contribution
of
emotional
or
immunological
systems
in
controlling
the
transition
between
acute
and
chronic
diseases.
Indeed,
it
could
be
that
the
disturbance
in
emotional
wellbeing
is
one
of
the
leading
causes
that
make
acute
inflammatory
response
transform
into
chronic
autoimmune
disorders.
Similarly,
change
in
the
immune
system
might
constitute
the
tipping
point
for
a
weak
emotional
state
to
become
a
chronic
and
morbid
mood
condition.
The
validation
of
this
hypothesis
would
lead
to
an
entirely
new
therapeutic
protocol
where
co-therapy
will
be
substituted
by
sequential
therapies.
Thus,
a
patient
with
high
risk
of
mental
disorders
will
be
given
treatment
for
the
mental
disorder
first
and
an
immuno-
modulatory
therapy
as
a
preventative
of
future
flares.
Similarly,
patients
with
autoimmune
diseases
will
be
treated
with
immunosuppressants
during
the
acute
phase
of
the
disease
and
then
kept
under
‘emotional
modula-
tors’
as
soon
as
remission
comes
up.
Clearly,
the
validity
of
such
protocols
will
require
several
clinical
trials
before
a
definite
answer
can
be
reached.
In
the
meantime,
I
hope
that
this
volume
on
immunomo-
dulation
will
convince
my
pharmacologist
colleagues
as
well
as
scientists
from
other
disciplines
to
‘open
their
mind’
and
wonder
if
the
disease
they
are
studying
could
also
be
looked
at
from
the
perspective
of
an
apparently
distant
area
of
research.
As
history
and
current
events
have
convincingly
shown
‘separation’
is
never
the
best
and
most
convenient
choice
to
address
a
problem.
In
life
as
in
science!
Conflict
of
interest
statement
Nothing
.declared.
Acknowledgements
I
am
very
grateful
to
Dr
Dianne
Cooper
and
Dr
Lucy
Norling
for
their
feedback
and
suggestions.
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MW:
The
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Cell
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121:503-504.
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Bosche
K,
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K,
Christians
U,
Witzke
O,
Engler
H,
Schedlowski
M,
Hadamitzky
M:
Neurobehavioral
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small
molecule-drug
immunosuppression.
Neuropharmacology
2015,
96:83-93.
3.
Fireman
M,
DiMartini
AF,
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SC,
Cozza
KL:
Immunosuppressants.
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2004,
45:354-360.
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Sarkar
S,
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M:
Antidepressant
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alfa-associated
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Andrade
C:
Antidepressant
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with
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J
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2014,
75:975-977.
Editorial
overview
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3
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Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Figure
1
Current Opinion in Pharmacology
Affective
Immunology:
where
immunity
and
emotions
converge.
Tag-cloud
analysis
of
the
most
common
terms
used
in
the
contributions
made
to
this
volume
of
Current
Opinion
in
Pharmacology
dedicated
to
Immunomodulation.
Terms
like
‘‘depression’’,
‘‘PTSD’’,
‘‘inflammation’’,
‘‘stress’’
and
‘‘cytokines’’
had
the
highest
score
(cited
more
than
70
times)
and
might
represent
the
common
feature
among
all
the
topics
that
have
been
explored.
Terms
like
‘‘microglia’’,
‘‘GSH’’
and
‘‘gut’’
were
the
least
used
(cited
10
times)
and
might
represent
themes
that
are
developing
or
are
more
relevant
to
specific
aspects.
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2016,
29:15
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4
Immunomodulation
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
Current
Opinion
in
Pharmacology
2016,
29:15
www.sciencedirect.com
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DM,
Ringel
Y,
Heyman
MB,
Foster
JA,
Bercik
P,
Shulman
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Versalovic
J,
Verdu
EF,
Dinan
TG,
Hecht
G
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Editorial
overview
D’Acquisto
5
COPHAR-1539;
NO.
OF
PAGES
5
Please
cite
this
article
in
press
as:
D’Acquisto
F:
Editorial
overview:
Immunomodulation:
Exploiting
the
circle
between
emotions
and
immunity:
impact
on
pharmacological
treatments,
Curr
Opin
Pharmacol
(2016),
http://dx.doi.org/10.1016/j.coph.2016.07.008
www.sciencedirect.com
Current
Opinion
in
Pharmacology
2016,
29:15
... Several studies (11,26,32,42,43,113,138) have highlighted the link between emotion and immunity. ...
... We think that the implications of these studies go beyond the simple duality of emotions and immunity as an example of body-mind continuum. Indeed, the ''mirroring effect'' that we have proposed to explain how emotions influence immune response and vice versa (26,42,43) might as well work for another system. ...
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Significance: The environment can elicit biological responses such as oxidative stress (OS) and inflammation as consequence of chemical, physical or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of oxidative stress or inflammation are critical in formulating mechanistic hypotheses. Recent advances. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess oxidative stress and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species, ROS) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. Critical issues: The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. Future directions: We propose to consider the role of biomarkers as signs and distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process.
... As a result, people suffering other hard conditions, like having had a traumatic episode, could not be allocated for treatment in a hospital; • The risk of spreading paranoia and fear for the neighbourhood as already evidenced by the increase in buying guns in the US;• The risk of a reduced response from the immunosystem by those people considering the diagnosis of COVID-19, which could be interpreted as a death penalty, given the current mass psychosis surrounding the virus. It is well known that the immunosystem has a strong association with the mood and the mind[23,24];• The risk of harming the economy, not only for the slowdown of some of the activities. Moreover, it can cause the waste in useless medical items (as already mentioned for Tamiflu) or for speculations present in the financial market due to possible predatory behaviours. ...
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Living in isolation is considered an emerging societal problem that negatively affects the physical wellbeing of its sufferers in ways that we are just starting to appreciate. This study investigates the immunomodulatory effects of social isolation in mice, utilising a two-week program of sole cage occupancy followed by the testing of immune-inflammatory resilience to bacterial sepsis. Our results revealed that mice housed in social isolation showed an increased ability to clear bacterial infection compared to control socially housed animals. These effects were associated with specific changes in whole blood gene expression profile and an increased production of classical pro-inflammatory cytokines. Interestingly, equipping socially isolated mice with artificial nests as a substitute for their natural huddling behaviour reversed the increased resistance to bacterial sepsis. Together these results suggest that the control of body temperature through social housing and huddling behaviour are important factors in the regulation of the host immune response to infection in mice and might provide another example of the many ways by which living conditions influence immunity.
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Within the central nervous system the traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. More recently, microglia have been found to be important for normal brain development, circuit refinement, and synaptic plasticity in ways that were previously unsuspected. Hence, the brain innate immune system appears to be key in all situations, ranging from physiology to pathology. This unique feature of microglia is established by the wide array of receptors it is equipped with to sense molecular patterns. This includes receptors to most if not all neurotransmitters, neuromodulators and purines. We here review novel, yet extensive literature on a new class of microglia modulators, namely bioactive fatty acids. These lipids are issued from metabolism of nutrients and can cross the blood brain barrier to reach the CNS. They appear to be direct modulators of microglial activity, triggering/inhibiting inflammatory processes or enhancing/inhibiting the ability of these cells to respond to hazardous agents.
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Increased body weight and metabolic disorder including insulin resistance, type 2 diabetes and cardiovascular complications together constitute metabolic syndrome. The pathogenesis of metabolic syndrome involves multitude of factors. A number of studies however indicate, with some conformity, that oxidative stress along with chronic inflammatory condition pave the way for the development of metabolic diseases. Oxidative stress, a state of lost balance between the oxidative and anti-oxidative systems of the cells and tissues, results in the over production of oxidative free radicals and reactive oxygen species (ROS). Excessive ROS generated could attack the cellular proteins, lipids and nucleic acids leading to cellular dysfunction including loss of energy metabolism, altered cell signalling and cell cycle control, genetic mutations, altered cellular transport mechanisms and overall decreased biological activity, immune activation and inflammation. In addition, nutritional stress such as that caused by high fat high carbohydrate diet also promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation, and decreased antioxidant system and reduced glutathione (GSH) levels. These changes lead to initiation of pathogenic milieu and development of several chronic diseases. Studies suggest that in obese person oxidative stress and chronic inflammation are the important underlying factors that lead to development of pathologies such as carcinogenesis, obesity, diabetes, and cardiovascular diseases through altered cellular and nuclear mechanisms, including impaired DNA damage repair and cell cycle regulation. Here we discuss the aspects of metabolic disorders-induced oxidative stress in major pathological conditions and strategies for their prevention and therapy.
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Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders.
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Endocannabinoids are bioactive lipids that have the potential to signal through cannabinoid receptors to modulate the functional activities of a variety of immune cells. Their activation of these seven-transmembranal, G protein-coupled receptors sets in motion a series of signal transductional events that converge at the transcriptional level to regulate cell migration and the production of cytokines and chemokines. There is a large body of data that supports a functional relevance for 2-arachidonoylglycerol (2-AG) as acting through the cannabinoid receptor type 2 (CB2R) to inhibit migratory activities for a diverse array of immune cell types. However, unequivocal data that supports a functional linkage of anandamide (AEA) to a cannabinoid receptor in immune modulation remains to be obtained. Endocannabinoids, as typical bioactive lipids, have a short half-life and appear to act in an autocrine and paracrine fashion. Their immediate effective action on immune function may be at localized sites in the periphery and within the central nervous system. It is speculated that endocannabinoids play an important role in maintaining the overall "fine-tuning" of the immune homeostatic balance within the host.
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There exists a bidirectional communication system between gastrointestinal tract and brain. Increasing evidence shows that gut microbiota can play a critical role in this communication, thus a concept of gut microbiota and brain axis is emerging. Here, we review recent findings in the relationship between intestinal microbes and brain function, such as anxiety, depression, stress, autism, learning and memory. We highlight the advances in modulating brain development and behavior by probiotics, prebiotics and diets through the gut microbiota-brain axis. A variety of mechanisms including immune, neural and metabolic pathways may be involved in the modulation of gut microbiota-brain axis. We also discuss some challenges in the future. A deeper understanding of the relationship between the gut bacteria and their hosts is implicated in developing microbial-based therapeutic strategies for brain disorders.