bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Окт. 16, 2023
Abstract
Microglia
and
astrocytes
play
an
important
role
in
the
neuroinflammatory
response
contribute
to
both
destruction
of
neighboring
tissue
as
well
resolution
inflammation
following
stroke.
These
reactive
glial
cells
are
highly
heterogeneous
at
transcriptomic
functional
level.
Depending
upon
stimulus,
microglia
mount
a
complex,
specific
composed
distinct
microglial
astrocyte
substates.
substates
ultimately
drive
landscape
initiation
recovery
from
adverse
stimulus.
In
one
state,
inflammation-
damage-induced
release
tumor
necrosis
factor
(TNF),
interleukin
1α
(IL1α),
complement
component
1q
(C1q),
together
‘TIC’.
This
cocktail
cytokines
drives
into
neurotoxic
(nRA)
substate.
nRA
substate
is
associated
with
loss
many
physiological
functions
(e.g.,
synapse
formation
maturation,
phagocytosis,
among
others),
gain-of-function
long-chain
fatty
acids
which
kill
cells.
Here
we
report
that
transgenic
removal
TIC
led
reduction
gliosis,
infarct
expansion,
worsened
deficits
acute
delayed
stages
Our
results
suggest
cytokines,
likely
nRAs
may
maintain
neuroinflammation
inhibit
motor
after
ischemic
first
this
paradigm
relevant
stroke
therapies
against
be
novel
means
treat
patients.
Since
evolutionarily
conserved
rodents
humans
present
multiple
neurodegenerative
diseases
injuries,
further
identification
mechanistic
will
lead
better
understanding
development
new
therapies.
Glia,
Год журнала:
2024,
Номер
72(6), С. 1016 - 1053
Опубликована: Янв. 4, 2024
Abstract
Microglia
play
key
roles
in
the
post‐ischemic
inflammatory
response
and
damaged
tissue
removal
reacting
rapidly
to
disturbances
caused
by
ischemia
working
restore
lost
homeostasis.
However,
modified
environment,
encompassing
ionic
imbalances,
disruption
of
crucial
neuron–microglia
interactions,
spreading
depolarization,
generation
danger
signals
from
necrotic
neurons,
induce
morphological
phenotypic
shifts
microglia.
This
leads
them
adopt
a
proinflammatory
profile
heighten
their
phagocytic
activity.
From
day
three
post‐ischemia,
macrophages
infiltrate
core
while
microglia
amass
at
periphery.
Further,
inflammation
prompts
metabolic
shift
favoring
glycolysis,
pentose‐phosphate
shunt,
lipid
synthesis.
These
shifts,
combined
with
intake,
drive
droplet
biogenesis,
fuel
anabolism,
enable
proliferation.
Proliferating
release
trophic
factors
contributing
protection
repair.
some
accumulate
lipids
persistently
transform
into
dysfunctional
potentially
harmful
foam
cells.
Studies
also
showed
that
either
display
impaired
apoptotic
cell
clearance,
or
eliminate
synapses,
viable
endothelial
Yet,
it
will
be
essential
elucidate
viability
engulfed
cells,
features
local
extent
damage,
temporal
sequence.
Ischemia
provides
rich
variety
region‐
injury‐dependent
stimuli
for
microglia,
evolving
time
generating
distinct
phenotypes
including
those
exhibiting
traits
others
showing
pro‐repair
features.
Accurate
profiling
phenotypes,
alongside
more
precise
understanding
associated
conditions,
is
necessary
step
serve
as
potential
foundation
focused
interventions
human
stroke.
Nature Neuroscience,
Год журнала:
2024,
Номер
27(8), С. 1505 - 1521
Опубликована: Июнь 21, 2024
Central
nervous
system
(CNS)
lesions
become
surrounded
by
neuroprotective
borders
of
newly
proliferated
reactive
astrocytes;
however,
fundamental
features
these
cells
are
poorly
understood.
Here
we
show
that
following
spinal
cord
injury
or
stroke,
90%
and
10%
border-forming
astrocytes
derive,
respectively,
from
proliferating
local
oligodendrocyte
progenitor
in
adult
mice
both
sexes.
Temporal
transcriptome
analysis,
single-nucleus
RNA
sequencing
immunohistochemistry
after
focal
CNS
injury,
mature
dedifferentiate,
proliferate
transcriptionally
reprogrammed
to
permanently
altered
new
states,
with
persisting
downregulation
molecules
associated
astrocyte-neuron
interactions
upregulation
wound
healing,
microbial
defense
stromal
immune
cells.
These
repair
share
morphologic
transcriptional
perimeningeal
limitans
the
predominant
source
re-establish
integrity
around
separating
neural
parenchyma
as
occurs
throughout
healthy
CNS.
Glia,
Год журнала:
2023,
Номер
71(8), С. 1960 - 1984
Опубликована: Апрель 17, 2023
Abstract
Neuroinflammation
is
a
hallmark
of
ischemic
stroke,
which
leading
cause
death
and
long‐term
disability.
Understanding
the
exact
cellular
signaling
pathways
that
initiate
propagate
neuroinflammation
after
stroke
will
be
critical
for
developing
immunomodulatory
therapies.
In
particular,
precise
mechanisms
inflammatory
in
clinically
relevant
hyperacute
period,
hours
have
not
been
elucidated.
We
used
RiboTag
technique
to
obtain
microglia
astrocyte‐derived
mRNA
transcripts
(4
h)
acute
(3
days)
period
as
these
two
cell
types
are
key
modulators
neuroinflammation.
Microglia
initiated
rapid
response
at
4
h
by
adopting
an
profile
associated
with
recruitment
immune
cells.
The
astrocyte
was
marked
stress
genes
transcription
factors,
such
Fos
Jun
,
involved
pro‐inflammatory
TNF‐α.
By
3
days,
shift
proliferative
state
astrocytes
strengthen
their
response.
days
partially
driven
upregulation
factors
C/EBPβ
Spi1
Rel
comprise
25%
upregulated
factor‐target
interactions.
Surprisingly,
few
sex
differences
across
all
groups
were
observed.
Expression
log
2
fold
data
sequenced
available
on
user‐friendly
website
researchers
examine
gene
changes
generate
hypotheses
targets.
Taken
together,
our
comprehensively
describe
astrocyte‐specific
translatome
identify
initiating
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 27, 2024
Molecular
pathways
mediating
systemic
inflammation
entering
the
brain
parenchyma
to
induce
sepsis-associated
encephalopathy
(SAE)
remain
elusive.
Here,
we
report
that
in
mice
during
first
6
hours
of
peripheral
lipopolysaccharide
(LPS)-evoked
(6
hpi),
plasma
level
adenosine
quickly
increased
and
enhanced
tone
central
extracellular
which
then
provoked
neuroinflammation
by
triggering
early
astrocyte
reactivity.
Specific
ablation
astrocytic
Gi
protein-coupled
A1
receptors
(A1ARs)
prevented
this
reactivity
reduced
levels
inflammatory
factors
(e.g.,
CCL2,
CCL5,
CXCL1)
astrocytes,
thereby
alleviating
microglial
reaction,
ameliorating
blood-brain
barrier
disruption,
immune
cell
infiltration,
neuronal
dysfunction,
depression-like
behaviour
mice.
Chemogenetic
stimulation
signaling
A1AR-deficent
astrocytes
at
2
4
hpi
LPS
injection
could
restore
behaviour,
highlighting
rather
than
microglia
as
drivers
neuroinflammation.
Our
results
identify
towards
an
important
pathway
driving
SAE
highlight
potential
targeting
A1ARs
for
therapeutic
intervention.
Frontiers in Molecular Neuroscience,
Год журнала:
2024,
Номер
16
Опубликована: Янв. 4, 2024
Microglia
and
astrocytes
play
an
important
role
in
the
neuroinflammatory
response
contribute
to
both
destruction
of
neighboring
tissue
as
well
resolution
inflammation
following
stroke.
These
reactive
glial
cells
are
highly
heterogeneous
at
transcriptomic
functional
level.
Depending
upon
stimulus,
microglia
mount
a
complex,
specific
composed
distinct
microglial
astrocyte
substates.
substates
ultimately
drive
landscape
initiation
recovery
from
adverse
stimulus.
In
one
state,
inflammation-
damage-induced
release
tumor
necrosis
factor
(TNF),
interleukin
1α
(IL1α),
complement
component
1q
(C1q),
together
"TIC."
This
cocktail
cytokines
drives
into
neurotoxic
(nRA)
substate.
nRA
substate
is
associated
with
loss
many
physiological
functions
(e.g.,
synapse
formation
maturation,
phagocytosis,
among
others),
gain-of-function
long-chain
fatty
acids
which
kill
cells.
Here
we
report
that
transgenic
removal
TIC
led
reduction
gliosis,
infarct
expansion,
worsened
deficits
acute
delayed
stages
Our
results
suggest
cytokines,
likely
nRAs
may
maintain
neuroinflammation
inhibit
motor
after
ischemic
first
this
paradigm
relevant
stroke
therapies
against
be
novel
means
treat
patients.
Since
evolutionarily
conserved
rodents
humans
present
multiple
neurodegenerative
diseases
injuries,
further
identification
mechanistic
will
lead
better
understanding
development
new
therapies.
CNS Neuroscience & Therapeutics,
Год журнала:
2024,
Номер
30(4)
Опубликована: Апрель 1, 2024
Abstract
Background
Alzheimer's
disease
(AD)
is
a
neurodegenerative
disorder
distinguished
by
swift
cognitive
deterioration
accompanied
distinctive
pathological
hallmarks
such
as
extracellular
Aβ
(β‐amyloid)
peptides,
neuronal
neurofibrillary
tangles
(NFTs),
sustained
neuroinflammation,
and
synaptic
degeneration.
The
elevated
frequency
of
AD
cases
its
proclivity
to
manifest
at
younger
age
present
pressing
challenge
in
the
quest
for
novel
therapeutic
interventions.
Numerous
investigations
have
substantiated
involvement
C/EBPβ
progression
pathology,
thus
indicating
potential
target
treatment.
Aims
Several
studies
demonstrated
an
elevation
expression
level
among
individuals
afflicted
with
AD.
Consequently,
this
review
predominantly
delves
into
association
between
disease,
elucidating
underlying
molecular
mechanism,
pointing
out
possibility
that
can
be
new
Methods
A
systematic
literature
search
was
performed
across
multiple
databases,
including
PubMed,
Google
Scholar,
so
on,
utilizing
predetermined
keywords
MeSH
terms,
without
temporal
constraints.
inclusion
criteria
encompassed
diverse
study
designs,
experimental,
case–control,
cohort
studies,
restricted
publications
English
language,
while
conference
abstracts
unpublished
sources
were
excluded.
Results
Overexpression
exacerbates
features
AD,
primarily
promoting
neuroinflammation
mediating
transcriptional
regulation
key
pathways,
δ‐secretase,
apolipoprotein
E4
(APOE4),
acidic
leucine‐rich
nuclear
phosphoprotein‐32A
(ANP32A),
transient
receptor
channel
1
(TRPC1),
Forkhead
BoxO
(FOXO).
Discussion
correlation
overexpression
development
along
mechanisms,
evident.
Investigating
pathways
through
which
regulates
reveals
numerous
vicious
cycle
exacerbating
disease.
Furthermore,
exacerbation
due
mechanism
not
limited
but
also
extends
other
diseases
amyotrophic
lateral
sclerosis
(ALS),
Parkinson's
(PD),
(MS).
Conclusion
accelerates
irreversible
pathophysiology.
Additionally,
plays
crucial
role
linked
some
engender
cycles,
leading
establishment
feedback
mechanisms.
To
sum
up,
targeting
could
hold
promise
strategy
only
degenerative
diseases.
Brain Behavior and Immunity,
Год журнала:
2023,
Номер
116, С. 269 - 285
Опубликована: Дек. 22, 2023
Microglia,
the
resident
immune
cells
of
central
nervous
system
(CNS),
play
a
major
role
in
damage
progression
and
tissue
remodeling
after
acute
CNS
injury,
including
ischemic
stroke
(IS)
spinal
cord
injury
(SCI).
Understanding
molecular
mechanisms
regulating
microglial
responses
to
may
thus
reveal
novel
therapeutic
targets
promote
repair.
Here,
we
investigated
tumor
necrosis
factor
receptor
2
(TNFR2),
transmembrane
previously
associated
with
pro-survival
neuroprotective
responses,
shaping
neuroinflammatory
environment
injury.
By
inducing
experimental
IS
SCI
Cx3cr1
Frontiers in Cellular Neuroscience,
Год журнала:
2024,
Номер
18
Опубликована: Март 14, 2024
Ischemic
stroke
is
a
major
disease
causing
death
and
disability
in
the
elderly
one
of
diseases
that
seriously
threaten
human
health
cause
great
economic
burden.
In
early
stage
ischemic
stroke,
neuronal
structure
destroyed,
resulting
or
damage,
release
variety
damage-associated
pattern
molecules
induces
an
increase
neuroglial
activation,
peripheral
immune
response,
secretion
inflammatory
mediators,
which
further
exacerbates
damage
to
blood-brain
barrier,
cerebral
edema,
microcirculatory
impairment,
triggering
secondary
brain
injuries.
After
acute
phase
various
cells
initiate
protective
effect,
released
step
by
contributes
repair
through
phenotypic
changes.
addition,
Central
Nervous
System
(CNS)
immunosuppression,
interaction
between
two
influences
outcome
stroke.
Therefore,
modulating
response
CNS
reduce
during
important
for
protection
function
long-term
recovery
after
expected
be
novel
therapeutic
strategy.
However,
there
are
fewer
studies
on
B-cells
protection,
may
play
dual
role
process,
understanding
this
cell
still
incomplete.
We
review
existing
mechanisms
B-cells,
development
provide
reference
adjuvant
drugs
targeting
injury.
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(1), С. 309 - 309
Опубликована: Янв. 1, 2025
Brain
ischemia
causes
disruption
in
cerebral
blood
flow
and
blood–brain
barrier
integrity,
which
are
normally
maintained
by
astrocyte
endfeet.
Emerging
evidence
points
to
dysregulation
of
the
translatome
during
ischemia,
but
its
effects
on
endfoot
unknown.
In
this
study,
we
aimed
investigate
early
a
rodent
reperfusion
model
stroke.
To
do
so,
immunoprecipitated
astrocyte-specific
tagged
ribosomes
(RiboTag
IP)
from
mechanically
isolated
brain
microvessels.
mice
subjected
middle
artery
occlusion
contralateral
controls,
sequenced
ribosome-bound
RNAs
perivascular
endfeet
identified
205
genes
that
were
differentially
expressed
after
ischemia.
The
main
biological
processes
associated
with
these
included
proteostasis,
inflammation,
cell
cycle/death,
metabolism.
Transcription
factors
whose
targets
enriched
amongst
upregulated
translating
HSF1,
master
regulator
heat
shock
response.
most
highly
HSF1-dependent
Hspa1a
Hspa1b,
encode
inducible
HSP70.
Using
qPCR,
Western
blot,
immunohistochemistry,
confirmed
HSP70
is
This
coincided
an
increase
ubiquitination
across
proteome
suggests
induces
proteostasis
These
findings
suggest
robust
response
proteotoxic
stress
Modulating
may
be
strategy
preserve
function
BBB
integrity
ischemic
