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.
Frontiers in Immunology,
Год журнала:
2018,
Номер
9
Опубликована: Фев. 5, 2018
Metabolism
in
immune
cells
is
no
longer
thought
of
as
merely
a
process
for
ATP
production,
biosynthesis
and
catabolism.
The
reprogramming
metabolic
pathways
upon
activation
also
the
production
metabolites
that
can
act
signalling
molecules.
Activated
dendritic
(DCs)
macrophages
have
an
altered
Krebs
cycle,
one
consequence
which
accumulation
both
citrate
succinate.
Citrate
exported
from
mitochondria
via
mitochondrial
carrier.
Cytosolic
metabolism
to
acetyl-coenzyme
A
(acetyl-CoA)
important
fatty-acid
synthesis
protein
acetylation,
been
linked
macrophage
DC
activation.
Citrate-derived
itaconate
has
direct
antibacterial
effect
shown
anti-inflammatory
agent,
inhibiting
succinate
dehydrogenase.
These
findings
identify
metabolite
effector
function.
A
paradox
of
tumor
immunology
is
that
tumor-infiltrating
lymphocytes
are
dysfunctional
in
situ,
yet
capable
stem
cell-like
behavior
including
self-renewal,
expansion,
and
multipotency,
resulting
the
eradication
large
metastatic
tumors.
We
find
overabundance
potassium
microenvironment
underlies
this
dichotomy,
triggering
suppression
T
cell
effector
function
while
preserving
stemness.
High
levels
extracellular
constrain
programs
by
limiting
nutrient
uptake,
thereby
inducing
autophagy
reduction
histone
acetylation
at
exhaustion
loci,
which
turn
produces
CD8+
cells
with
improved
vivo
persistence,
clearance.
This
mechanistic
knowledge
advances
our
understanding
dysfunction
may
lead
to
novel
approaches
enable
development
enhanced
strategies
for
cancer
immunotherapy.
