bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 2, 2024
Abstract
The
regulation
of
inflammatory
gene
expression
involves
complex
interactions
between
transcription
factors
(TFs),
signaling
pathways
and
epigenetic
chromatin-mediated
mechanisms.
This
study
investigated
mechanisms
by
which
IFN-γ-mediated
priming
augments
TLR-induced
NF-κB
target
genes
in
primary
human
monocytes.
IFN-γ
enhanced
the
signature
such
as
IL6
,
TNF
IL1B
CXCL10
when
monocytes
were
exposed
to
various
TLR
agonists.
RNA-seq
analysis
identified
synergistically
activated
LPS,
enriched
pathways.
Similar
synergistic
activation
was
observed
with
TLR1/2
agonist
PAM3CYS,
suggesting
a
shared
regulatory
mechanism.
ATAC-seq
revealed
that
ligands
induce
IRF1
TF
activity
independently
IFN-γ.
JAK1/2
inhibitor
(iJAK)
treatment
reduced
protein
levels,
especially
IFN-γ-treated
monocytes,
but
not
LPS-stimulated
LPS-induced
may
compensate
for
loss
IFN-γ-induced
IRF1.
We
applied
CRISPR-Cas9
knock
out
found
abrogates
key
genes,
pivotal
role
genetic
data
corroborated
CUT&RUN
showing
resistance
binding
JAK
inhibition
under
(IFN-γ
+
LPS)
costimulated
conditions,
co-occupancy
sites
NF-κB.
enhances
our
understanding
regulation,
highlighting
player
potential
therapeutic
diseases.
IL-1β-expressing
macrophages
have
been
described
in
rheumatoid
arthritis
(RA),
immune
checkpoint
inhibitor-induced
inflammatory
(ICI-arthritis),
and
pancreatic
cancer
proposed
to
be
pathogenic.
In
RA
IL-1β+
express
a
TNF+PGE2
(TP)
gene
expression
signature
induced
by
cooperation
between
PGE2
TNF
signaling,
but
mechanisms
that
induce
these
cells
the
extent
which
they
contribute
arthritic
phenotypes
are
not
known.
this
study
we
used
an
integrated
transcriptomic
epigenomic
analysis
primary
human
monocytes
PGE2-TNF
crosstalk,
how
it
is
regulated
IFN-γ,
as
occurs
synovial
macrophages.
We
identified
(TNF
+
PGE2)-
enriched
IL1β+
macrophage
subset
defined
scRNAseq
includes
genes
pathogenic
IL-1,
Notch
neutrophil
chemokine
pathways.
A
similar
was
apparent
newly
ICI-arthritis.
TP
distinct
from
canonical
NF-κB
target
such
,
IL6
IL12B
activated
of
PGE2-induced
AP-1,
CEBP
NR4A
family
transcription
factors
with
TNF-induced
activity.
Unexpectedly,
IFN-γ
suppressed
induction
activity
ablate
genes,
while
promoting
T
cell
chemokines
like
CXCL10.
These
results
reveal
basis
for
synergistic
TNF,
novel
regulatory
axis
whereby
oppose
each
other
determine
balance
two
programs
relevant
IL-1β-expressing
macrophages
have
been
described
in
rheumatoid
arthritis
(RA),
immune
checkpoint
inhibitor-induced
inflammatory
(ICI-arthritis),
and
pancreatic
cancer
proposed
to
be
pathogenic.
In
RA
IL-1β+
express
a
TNF+PGE2
(TP)
gene
expression
signature
induced
by
cooperation
between
PGE2
TNF
signaling,
but
mechanisms
that
induce
these
cells
the
extent
which
they
contribute
arthritic
phenotypes
are
not
known.
this
study
we
used
an
integrated
transcriptomic
epigenomic
analysis
primary
human
monocytes
PGE2-TNF
crosstalk,
how
it
is
regulated
IFN-γ,
as
occurs
synovial
macrophages.
We
identified
(TNF
+
PGE2)-
enriched
IL1β+
macrophage
subset
defined
scRNAseq
includes
genes
pathogenic
IL-1,
Notch
neutrophil
chemokine
pathways.
A
similar
was
apparent
newly
ICI-arthritis.
TP
distinct
from
canonical
NF-κB
target
such
,
IL6
IL12B
activated
of
PGE2-induced
AP-1,
CEBP
NR4A
family
transcription
factors
with
TNF-induced
activity.
Unexpectedly,
IFN-γ
suppressed
induction
activity
ablate
genes,
while
promoting
T
cell
chemokines
like
CXCL10.
These
results
reveal
basis
for
synergistic
TNF,
novel
regulatory
axis
whereby
oppose
each
other
determine
balance
two
programs
relevant
The Journal of Experimental Medicine,
Journal Year:
2025,
Volume and Issue:
222(4)
Published: Feb. 28, 2025
BCG
is
the
oldest
vaccine
in
continuous
use.
While
current
intradermal
vaccination
regimens
confer
limited
protection
outside
context
of
pediatric
extrapulmonary
tuberculosis
(TB),
promising
new
data
indicate
that
when
administered
mucosally
or
intravenously
at
a
higher
dose,
can
induce
sterilizing
immunity
against
pulmonary
TB
nonhuman
primates.
also
known
to
promote
nonspecific
host
resistance
variety
unrelated
infections
and
standard
immunotherapy
for
bladder
cancer,
suggesting
this
innate
immune
function
may
contribute
its
protective
role
TB.
Here,
we
propose
both
mycobacterial-specific
off-target
effects
depend
on
interplay
adaptive
cells
cytokines
they
produce,
elucidation
interaction
should
be
major
strategy
development
more
effective
BCG-based
vaccines
immunotherapies.
Communications Biology,
Journal Year:
2025,
Volume and Issue:
8(1)
Published: May 30, 2025
Patients
suffering
from
rheumatoid
arthritis
(RA)
and
related
autoimmune
joint
diseases
exhibit
cyclic
episodes
of
resolution
exacerbation
inflammation,
referred
to
as
flares.
Fibroblast-like
synoviocytes
(FLSs)
that
are
epigenetically
transformed
by
chronic
inflammation
implicated
the
orchestrators
these
In
this
study,
we
compared
cellular
molecular
features
FLSs
during
inflammatory
phases
RA
progression.
We
performed
histopathological
evaluations
joints
an
inducible
tumor
necrosis
factor-alpha
(TNF-α)
transgenic
mouse
model
reveal
phenotypic
hallmarks
including
synovial
hyperplasia,
increased
angiogenesis,
macrophage
infiltration,
were
all
reversed
upon
initiation
resolution.
However,
phase
exhibited
a
transcriptomic
signature
reminiscent
highly
state.
They
G0/G1
cell
cycle
arrest
accompanied
reduced
viability.
addition,
factors
secreted
FLSs,
induced
death,
decreased
angiogenic
potential
in
human
microvascular
umbilical
cord
endothelial
cells.
These
findings
indicate
secretome
impairs
function
suggest
understanding
interaction
between
cells
is
essential
for
achieving
complete
remission.
Journal of Leukocyte Biology,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 10, 2024
Macrophage
activation
syndrome
(MAS)
is
characterized
by
multi-lineage
cytopenias,
hypercytokinemia,
and
tissue
hemophagocytosis.
Transcription
factor
Nrf2
a
master
regulator
of
redox
homeostasis.
In
this
work
we
aim
to
investigate
the
role
in
murine
hyperinflammation
mechanisms
which
red
blood
cell
products
regulates
pro-inflammatory
cytokine
production.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 12, 2024
Abstract
IL-1β-expressing
macrophages
have
been
described
in
rheumatoid
arthritis
(RA),
immune
checkpoint
inhibitor-induced
inflammatory
(ICI-arthritis),
and
pancreatic
cancer
proposed
to
be
pathogenic.
In
RA
IL-1β+
express
genes
cooperatively
induced
by
PGE2
TNF
signaling,
but
mechanisms
that
induce
these
cells
the
extent
which
they
contribute
arthritic
phenotypes
are
not
known.
this
study
we
used
an
integrated
transcriptomic
epigenomic
analysis
primary
human
monocytes
PGE2-TNF
crosstalk,
how
it
is
regulated
IFN-γ,
as
occurs
synovial
macrophages.
We
identified
a
+
(TP)
gene
expression
signature
enriched
previously
IL1β+
monocytic
subset
defined
scRNAseq
includes
pathogenic
IL-1,
Notch
neutrophil
chemokine
pathways.
A
similar
TP
was
apparent
macrophage
newly
ICI-arthritis.
Reference
mapping
revealed
ICI-arthritis
myeloid
map
primarily
onto
four
clusters,
extends
beyond
subsets
of
adjacent
suggestive
new
functional
monocyte
subset.
distinct
from
canonical
NF-κB
target
such
,
IL6
IL12B
activated
cooperation
PGE2-induced
AP-1,
CEBP
NR4A
family
transcription
factors
with
TNF-induced
activity.
Unexpectedly,
IFN-γ
suppressed
induction
activity
ablate
genes,
while
promoting
T
cell
chemokines
like
CXCL10.
The
opposing
cross-regulation
IFN
signaling
vitro
reflected
vivo
mutually
exclusive
signatures
different
clusters
monocytes.
These
results
reveal
basis
for
synergistic
TNF,
novel
regulatory
axis
whereby
oppose
each
other
determine
balance
between
two
programs
relevant