Cell Metabolism,
Год журнала:
2019,
Номер
30(6), С. 1055 - 1074.e8
Опубликована: Ноя. 7, 2019
Accumulation
of
lactate
in
the
tissue
microenvironment
is
a
feature
both
inflammatory
disease
and
cancer.
Here,
we
assess
response
immune
cells
to
context
chronic
inflammation.
We
report
that
accumulation
inflamed
contributes
upregulation
transporter
SLC5A12
by
human
CD4+
T
cells.
SLC5A12-mediated
uptake
into
induces
reshaping
their
effector
phenotype,
resulting
increased
IL17
production
via
nuclear
PKM2/STAT3
enhanced
fatty
acid
synthesis.
It
also
leads
cell
retention
as
consequence
reduced
glycolysis
Furthermore,
antibody-mediated
blockade
ameliorates
severity
murine
model
arthritis.
Finally,
propose
lactate/SLC5A12-induced
metabolic
reprogramming
distinctive
lymphoid
synovitis
rheumatoid
arthritis
patients
potential
therapeutic
target
disorders.
Nature Communications,
Год журнала:
2021,
Номер
12(1)
Опубликована: Июль 1, 2021
Abstract
Emerging
data
demonstrate
that
the
activity
of
immune
cells
can
be
modulated
by
microbial
molecules.
Here,
we
show
short-chain
fatty
acids
(SCFAs)
pentanoate
and
butyrate
enhance
anti-tumor
cytotoxic
T
lymphocytes
(CTLs)
chimeric
antigen
receptor
(CAR)
through
metabolic
epigenetic
reprograming.
We
in
vitro
treatment
CTLs
CAR
with
increases
function
mTOR
as
a
central
cellular
sensor,
inhibits
class
I
histone
deacetylase
activity.
This
reprogramming
results
elevated
production
effector
molecules
such
CD25,
IFN-γ
TNF-α,
significantly
enhances
antigen-specific
ROR1-targeting
syngeneic
murine
melanoma
pancreatic
cancer
models.
Our
shed
light
onto
may
used
for
enhancing
immunity.
Collectively,
identify
two
SCFAs
therapeutic
utility
context
immunotherapy.
Cell Reports,
Год журнала:
2018,
Номер
22(6), С. 1509 - 1521
Опубликована: Фев. 1, 2018
To
fulfill
bioenergetic
demands
of
activation,
T
cells
perform
aerobic
glycolysis,
a
process
common
to
highly
proliferative
in
which
glucose
is
fermented
into
lactate
rather
than
oxidized
mitochondria.
However,
the
signaling
events
that
initiate
glycolysis
remain
unclear.
We
show
cell
activation
rapidly
induces
independent
transcription,
translation,
CD28,
and
Akt
not
involving
increased
uptake
or
activity
glycolytic
enzymes.
Rather,
TCR
promotes
pyruvate
dehydrogenase
kinase
1
(PDHK1),
inhibiting
mitochondrial
import
facilitating
breakdown
lactate.
Inhibition
PDHK1
reveals
this
switch
required
acutely
for
cytokine
synthesis
but
dispensable
cytotoxicity.
Functionally,
modulated
via
dehydrogenase,
represses
mRNA
translation
when
disengaged.
Our
data
provide
mechanistic
insight
metabolic
contribution
effector
function
suggest
may
be
finely
tuned
through
modulation
activity.
FEBS Journal,
Год журнала:
2020,
Номер
287(16), С. 3350 - 3369
Опубликована: Апрель 7, 2020
The
inflammatory
response
involves
the
activation
of
several
cell
types
to
fight
insults
caused
by
a
plethora
agents,
and
maintain
tissue
homoeostasis.
On
one
hand,
cells
involved
in
pro‐inflammatory
response,
such
as
M1
macrophages,
Th1
Th17
lymphocytes
or
activated
microglia,
must
rapidly
provide
energy
fuel
inflammation,
which
is
essentially
accomplished
glycolysis
high
lactate
production.
other
regulatory
T
M2
are
immune
regulation
resolution
preferentially
use
fatty
acid
oxidation
through
TCA
cycle
main
source
for
Here,
we
discuss
impact
glycolytic
metabolism
at
different
steps
response.
Finally,
review
wide
variety
molecular
mechanisms
could
explain
relationship
between
metabolites
phenotype,
including
signalling
events,
epigenetic
remodelling,
post‐transcriptional
post‐translational
modifications.
Inflammatory
processes
common
feature
many
age‐associated
diseases,
cardiovascular
neurodegenerative
disorders.
finding
that
immunometabolism
be
master
regulator
inflammation
broadens
avenue
treating
inflammation‐related
pathologies
manipulation
vascular
metabolism.
Cell Metabolism,
Год журнала:
2019,
Номер
30(6), С. 1055 - 1074.e8
Опубликована: Ноя. 7, 2019
Accumulation
of
lactate
in
the
tissue
microenvironment
is
a
feature
both
inflammatory
disease
and
cancer.
Here,
we
assess
response
immune
cells
to
context
chronic
inflammation.
We
report
that
accumulation
inflamed
contributes
upregulation
transporter
SLC5A12
by
human
CD4+
T
cells.
SLC5A12-mediated
uptake
into
induces
reshaping
their
effector
phenotype,
resulting
increased
IL17
production
via
nuclear
PKM2/STAT3
enhanced
fatty
acid
synthesis.
It
also
leads
cell
retention
as
consequence
reduced
glycolysis
Furthermore,
antibody-mediated
blockade
ameliorates
severity
murine
model
arthritis.
Finally,
propose
lactate/SLC5A12-induced
metabolic
reprogramming
distinctive
lymphoid
synovitis
rheumatoid
arthritis
patients
potential
therapeutic
target
disorders.