Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases

Abstract

The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.

Full text

Disponible
en
ligne
sur
www.sciencedirect.com
Médecine
et
maladies
infectieuses
43
(2013)
100–107
General
review
Regulation
of
oxidative
stress
by
Nrf2
in
the
pathophysiology
of
infectious
diseases
Régulation
du
stress
oxydant
par
Nrf2
dans
la
physiopathologie
des
maladies
infectieuses
T.B.
Deramaudta,∗,
C.
Dillb,c,
M.
Bonaya,d
aEA
4497,
équipe
handicap,
motricité
et
immunité,
faculté
des
sciences
de
la
santé
Paris-Île-de-France-Ouest,
université
de
Versailles
Saint-Quentin-en-Yvelines,
2,
avenue
de
la
Source-de-la-Bièvre,
78180
Montigny-le-Bretonneux,
France
bInserm,
UMR
787,
105,
boulevard
de
l’Hôpital,
75013
Paris,
France
cDépartement
STAPS,
faculté
des
sciences
de
la
santé
Paris-Île-de-France-Ouest,
université
de
Versailles
Saint-Quentin-en-Yvelines,
55,
avenue
de
Paris,
78000
Versailles,
France
dService
de
physiologie-explorations
fonctionnelles,
hôpital
Ambroise-Paré,
AP–HP,
Boulogne,
France
Received
28
December
2012;
received
in
revised
form
4
February
2013;
accepted
5
February
2013
Available
online
15
March
2013
Abstract
The
innate
immune
system,
including
phagocytic
cells,
is
the
first
line
of
defense
against
pathogens.
During
infection
by
microorganisms
such
as
viruses,
bacteria,
or
parasites,
phagocytic
cells
produce
an
excess
of
oxidants,
a
crucial
process
for
the
clearance
of
pathogens.
This
increase
in
oxidants
creates
an
imbalance
between
oxidants
and
endogenous
antioxidants.
Left
unchecked,
this
acute
or
chronic
oxidative
stress
can
lead
to
apoptotic
cell-death
and
oxidative
stress-induced
diseases
including
neurodegenerative
and
cardiovascular
disorders,
premature
aging,
secondary
infections,
and
cancer.
The
activation
of
nuclear
factor
E2-related
factor
2
(Nrf2)
is
an
efficient
antioxidant
defensive
mechanism
used
by
host
cells
to
counteract
oxidative
stress.
The
transcription
factor
Nrf2
has
been
identified
as
the
master
regulator
of
several
hundred
of
genes
involved
in
the
antioxidant
defense
response.
The
review
objectives
were
to
collect
recent
findings
on
the
contribution
of
oxidative
stress
to
complications
of
infection,
and
to
highlight
the
beneficial
impact
of
antioxidants
in
reducing
inflammation
and
oxidant-related
tissue
damage.
Furthermore,
a
direct
relationship
between
infection
and
decline
in
Nrf2
activity
has
been
demonstrated.
Thus,
an
interesting
therapeutic
approach
in
disease
prevention
and
treatment
of
stress-related
diseases
may
consist
in
optimizing
antibiotic
or
antiviral
therapy
with
a
combination
of
Nrf2
inducer
treatment.
©
2013
Elsevier
Masson
SAS.
All
rights
reserved.
Keywords:
Antioxidants;
Nrf2;
Oxidative
stress;
Infection;
ROS
Résumé
Le
système
immunitaire
inné,
composé
de
cellules
phagocytaires,
est
la
première
ligne
de
défense
contre
l’infection
par
des
agents
pathogènes.
Lors
d’infections
par
les
microorganismes
tels
que
les
virus,
les
bactéries
ou
les
parasites,
les
cellules
phagocytaires
produisent
en
excès
des
agents
oxydants.
Ce
déséquilibre
entre
oxydants
et
antioxydants
endogènes
est
un
processus
crucial
dans
l’élimination
des
pathogènes.
En
absence
de
contrôle,
ce
stress
oxydant
aigu
ou
chronique
peut
mener
à
la
mort
cellulaire
programmée,
ou
apoptose,
et
au
développement
de
maladies
telles
que
les
troubles
neurodégénératifs
et
cardiovasculaires,
le
vieillissement
prématuré,
les
infections
secondaires
et
le
cancer.
Un
mécanisme
antioxydant
efficace,
utilisé
par
les
cellules
pour
combattre
le
stress
oxydant,
consiste
à
activer
le
facteur
de
transcription
nuclear
factor
E2-related
factor
2
ou
Nrf2.
Nrf2
est
le
coordinateur
de
plusieurs
centaines
de
gènes
impliqués
dans
la
réponse
antioxydante.
Cette
revue
vise
à
réunir
les
études
récentes
sur
la
contribution
du
stress
oxydant
dans
les
complications
liées
à
l’infection
pathogénique
et
à
mettre
en
évidence
le
rôle
des
antioxydants
sur
la
diminution
de
l’inflammation
et
des
dommages
tissulaires
causés
par
les
oxydants.
De
plus,
un
lien
direct
entre
infection
et
diminution
de
l’activité
de
Nrf2
a
été
démontré.
Il
en
résulte
qu’une
approche
thérapeutique
intéressante
pour
prévenir
et
traiter
les
maladies
induites
par
le
stress
oxydant
consisterait
à
optimiser
les
effets
de
la
thérapie
antivirale
ou
antibiotique
par
l’association
à
un
activateur
spécifique
de
Nrf2.
©
2013
Elsevier
Masson
SAS.
Tous
droits
réservés.
Mots
clés
:
Antioxydants
;
Nrf2
;
Stress
oxydant
;
Infection
;
ROS
∗Corresponding
author.
E-mail
address:
therese.deramaudt@uvsq.fr
(T.B.
Deramaudt).
0399-077X/$
–
see
front
matter
©
2013
Elsevier
Masson
SAS.
All
rights
reserved.
http://dx.doi.org/10.1016/j.medmal.2013.02.004

T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
101
1.
Introduction
Microorganisms
such
as
bacteria,
viruses,
and
parasites
are
environmental
agents
that
invade
the
host
organism
through
var-
ious
routes
of
entry:
blood,
respiratory,
digestive,
sexual,
and
urogenital
systems.
The
innate
immune
response
is
the
host’s
first
line
of
defense
against
invading
pathogens.
The
propen-
sity
of
microbial
infection
to
proliferate
will
depend
on
factors
such
as
pathogen
virulence
and
load,
as
well
as
the
immune
defense
system
of
the
infected
host,
which
may
be
weakened
by
a
pre-existing
condition
or
drug
intake.
The
physiological
inflammatory
response
triggered
by
expo-
sure
to
the
pathogenic
microorganism
consists
in
stimulating
and
sending
inflammatory
cells,
such
as
macrophages
and
neu-
trophils,
to
the
area
of
aggression.
The
pathogens
are
engulfed
by
phagocytosis
into
phagosomal
structures
which
undergo
mat-
uration
by
fusion
with
early
and
late
endosomes,
and
finally
with
lysosomes.
Lysosomal
vesicles
include
oxidants,
including
reac-
tive
oxygen
species
(ROS)
and
reactive
nitrogen
species
(RNS),
compounds
known
for
their
microbicidal
activity
and
essential
elements
in
the
physiological
cellular
response
to
inflammation
[1].
Microbial
infection
often
causes
two
responses
from
the
host
cell:
an
elevated
production
of
oxidants
and
an
antioxidant
response.
The
excess
in
oxidants,
if
unchecked,
becomes
deleterious
to
the
cells
and
is
responsible
for
acute
or
chronic
oxidative
stress
that
can
lead
to
apoptotic
cell-death
and
tissue
damage.
Oxidative
stress
is
a
critical
factor
in
the
pathogenesis
of
a
wide
array
of
diseases,
including
neurodegenerative
disorders
such
as
Alzheimer’s
and
Parkinson’s
diseases
[2],
cardiovascular
and
pulmonary
disorders
[3,4],
premature
aging
[5],
primary
and
secondary
infections,
and
carcinogenesis
[6].
The
excess
of
oxidants
is
counterbalanced
by
the
greater
pro-
duction
of
oxidant
scavengers
and
antioxidant
enzymes.
The
oxidant
scavenger
group
includes
reduced
glutathione,
vitamins
A,
E,
and
C,
and
the
enzymatic
group
includes
superoxide
dismutase
and
phase
II
enzymes
such
as
NADPH
quinone
oxi-
doreductase
1
(NQO-1),
epoxyde
hydrolase
(EPHX),
and
Heme
oxygenase-1
(HO-1).
Most
genes
coding
for
cytoprotective
and
detoxifying
enzymes
are
regulated
by
transcription
factors
such
as
Nrf2,
AP-1
and
NF-␬B.
Nuclear
factor
E2-related
factor
2
(Nrf2)
is
the
key
regulator
of
expression
levels
for
more
than
100
genes
coding
for
antioxidants
via
the
antioxidant
response
elements
(ARE)
located
in
their
upstream
promoter
region.
We
will
review
the
potential
benefit
of
reducing
inflammation
and
tissue
damage
by
restoring
the
expression
of
antioxidants.
There
is
increasing
evidence
concerning
the
important
role
of
Nrf2
signaling
in
the
progression
of
a
variety
of
oxidative
stress-
related
human
diseases;
targeting
Nrf2
may
be
a
promising
therapeutic
strategy
to
prevent
oxidative
damage
during
infec-
tion.
2.
Infection
and
oxidative
stress
During
infection,
microorganisms
are
detected,
engulfed,
and
then
phagocytized
by
inflammatory
cells
including
macrophages,
neutrophils,
and
dendritic
cells.
Pathogens
activate
the
expression
of
NADPH
oxidase
complex
and
nitric
oxide
synthase
in
phagocytic
cells,
leading
to
an
increased
pro-
duction
of
ROS
and
RNS.
This
process,
crucial
for
pathogen
clearance,
occurs
in
many
infections
and
is
known
as
an
oxida-
tive
burst
or
respiratory
burst.
Oxidative
stress
is
the
consequence
of
an
imbalance
between
oxidants
and
antioxidants
in
cells.
Free
radicals,
such
as
ROS
and
RNS,
are
highly
unstable
and
react
with
biological
macro-
molecules,
thus
inflicting
damage
to
DNA,
proteins,
and
lipids.
ROS
include
by-product
metabolites
from
partially
reduced
oxygen,
including
superoxide
anion,
hydrogen
peroxide,
and
hydroxyl
radicals.
Oxidants
activate
the
redox-sensitive
NF-␬B
signaling
pathway,
which
induces
the
expression
of
cell
adhe-
sion
receptors,
pro-inflammatory
cytokines,
and
chemokines,
involved
in
the
production
of
free
radicals
and
persistence
of
inflammation.
Cells
activate
a
battery
of
cytoprotective
and
antioxidant
defense
mechanisms
to
maintain
a
redox
homeosta-
sis,
including
activation
of
Nrf2,
the
major
inducible
enhancer
of
ARE-mediated
phase
II
enzymes
(Fig.
1).
The
role
of
oxidative
stress
in
infection
and
dissemination
of
pathogen
is
only
partially
understood.
The
well-accepted
notion
that
an
oxidant
burst
is
generated
by
infected
immune
or
epithe-
lial
cells
for
pathogen
eradication
has
been
altered
by
evidence
suggesting
that
it
has
a
more
controversial
role.
Microorgan-
isms,
such
as
Trypanosoma
cruzi,
Human
immunodeficiency
virus
(HIV),
or
Mycobacterium
tuberculosis,
seem
to
be
able
to
survive
and
even
thrive
in
an
oxidative
environment.
3.
Nrf2
signaling
pathway
Nrf2
is
a
transcription
factor,
first
identified
in
1994,
that
belongs
to
the
Cap’n’
collar
basic
leucin
zipper
family;
it
is
ubiq-
uitously
expressed
in
all
human
tissues
[7].
It
includes
six
highly
conserved
domains
named
Neh
(Nrf2-ECH
homology)
1
to
Neh
6.
Nrf2
has
a
significant
action
in
adaptive
responses
to
oxida-
tive
stress,
by
interacting
with
ARE
sequences
of
antioxidant
and
cytoprotective
genes.
NRF2
is
sequestered
in
the
cytoplasm
by
interaction
with
Kelch-like
ECH-associated
protein
1
(Keap1)
in
normal
physiological
conditions.
The
Nrf2/Keap1
complex
is
rapidly
degraded
by
the
ubiquitin-proteasome
system
via
the
Keap1-Cullin-3
based
E3
ligase
complex
[8].
Therefore,
Keap1
negatively
regulates
Nrf2
by
blocking
Nrf2
translocation
to
the
nucleus
and
by
promoting
its
degradation.
Some
authors
recently
reported
that
Caveolin-1
(Cav-1)
was
a
Keap1-independent
inhibitor
of
Nrf2.
Cav-1,
a
scaffolding
protein
that
contributes
to
vesicular
trafficking,
inhibits
two
enzymes
involved
in
cellu-
lar
redox
homeostasis,
HO-1
and
thioredoxin
reductase
I
[9,10].
Cav-1
can
interact
directly
with
Nrf2
in
the
nucleus
and
in
the
cytoplasm.
The
overexpression
of
Cav-1
in
lung
epithelial
cells
inhibited
Nrf2
activity
and
consequently
reduced
the
expression
levels
of
antioxidant
enzymes
[11].
During
chemical
sensing
of
electrophiles
or
oxidants
by
Keap1,
Nrf2
is
released
and
is
phosphorylated
by
kinases
from
the
MAPK
signaling
pathway
such
as
ERK,
p38,
JNK
proteins,
and
phosphatidylinositol-3
kinase
[12].
Nrf2
is
then
removed
from
the
degradation
process
by
translocation
to
and
accumula-
tion
in
the
nucleus,
where
it
heterodimerizes
with
transcription

102
T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
Fig.
1.
Infection
promoting
oxidative
stress-mediated
diseases.
Infection
promouvant
les
maladies
liées
au
stress
oxydant.
factors
such
as
proteins
from
the
AP-1
family,
Maf,
c-Jun,
and
c-Fos
[13].
The
cofactor
complex
binds
specifically
to
the
ARE
sequences
of
a
wide
range
of
antioxidant
genes
coding
for
antioxidant
enzymes,
such
as
NADPH
quinone
oxidoreductase-
1,
epoxide
hydrolase-1,
HO-1,
UDP-glucuronyl
transferase,
glutathione-S-transferases
[14].
An
Nrf2
switch
off
mechanism,
involving
GSK-3␤
kinase,
is
activated
to
turn
off
the
expression
of
the
targeted
proteins.
The
phosphorylation
of
Fyn
by
GSK-3␤
induces
its
nuclear
import.
Then,
the
activated
Fyn
phosphorylates
Nrf2
at
tyrosine
568,
triggering
Nrf2
export
from
the
nucleus
to
the
cytoplasm,
where
it
is
subsequently
degraded
by
the
ubiquitin-proteasome
system
[15].
Furthermore,
Rada
et
al.
suggested
very
recently
the
hypothesis
of
a
novel
Keap1-independent
pathway
for
Nrf2
degradation,
which
requires
phosphorylation
by
GSK-3␤
of
ser-
ine
residues
in
the
Neh6
domain
of
Nrf2.
Phosphorylated
Nrf2
is
then
excluded
from
the
nucleus,
and
subject
to
ubiquitination
via
a
␤-TrCP/Cullin
1
E3
ligase
complex
[16].
It
is
well
established
that
the
Nrf2-ARE
signaling
pathway
is
regulated
via
post-translational
modifications,
but
there
is
some
compelling
new
evidence
that
epigenetic
mechanisms
[17]
or
polymorphism
[18]
may
modulate
the
transcriptional
activity
of
the
Nrf2
promoter.
4.
Nrf2
in
bacterial
infections
Sepsis
is
a
leading
cause
of
mortality
and
morbidity
world-
wide,
with
a
probably
underestimated
figure
of
1.8
million
cases
per
year.
Sepsis
is
a
life-threatening
condition
due
to
the
deregulation
of
the
host’s
systemic
immune
response
to
bacterial,
fungal,
or
viral
infections
causing
multiple
organ
failure,
and
eventually
death.
Nrf2−/−mice
were
more
sen-
sitive
to
LPS-induced
septic
shock
than
wild-type
mice.
Nrf2−/−mice,
exposed
to
sub-lethal
doses
of
LPS,
developed
lung
inflammation
associated
with
increased
levels
of
TNF-
␣,
pro-inflammatory
cytokines
and
chemokines,
and
NADPH
oxidase-dependent
ROS
generation,
compared
to
wild-type
mice.
Furthermore,
Nrf2−/−mice
had
a
higher
death
rate
when
exposed
to
lethal
dose
of
LPS
[19].
Moreover,
Nrf2−/−mice
were
more
sensitive
to
Staphylococcus
aureus
sepsis,
even
in
the
presence
of
carbon
monoxide
(CO),
an
Nrf2-dependent
HO-1
inducer.
CO-treated
wild-type
mice
had
a
higher
S.
aureus-
induced
sepsis
survival
rate,
due
to
activation
of
Nrf2
and
AKT
signaling
[20].
Nrf2−/−mice,
infected
with
S.
aureus
by
inhala-
tion,
had
a
lower
survival
rate
compared
to
wild-type
mice,
in
an
acute
lung
injury
murine
model.
Wild-type
mice
presented
an
increase
in
HO-1,
anti-inflammatory
IL-10,
and
mitochondrial
biogenesis,
and
a
decrease
in
pro-inflammatory
markers
[21].
Furthermore,
during
sepsis,
GSH
is
depleted
and
ROS
strongly
stimulates
the
expression
of
activating
transcription
fac-
tor
3
(ATF3)
via
activation
of
Nrf2.
ATF3
is
required
to
protect
against
endotoxinic
shock.
But
ATF3
expression
is
also
corre-
lated
with
an
increased
sensitivity
to
secondary
infections,
due
to
the
inhibition
of
interleukin
6
transcriptional
expression
[22].
5.
Nrf2
in
mycobacterial
infections
M.
tuberculosis,
the
causative
agent
of
tuberculosis,
is
a
major
source
of
morbidity
and
mortality
worldwide.
It
is
a
highly
contagious
pathogen
that
affects
preferentially
the
respiratory
tract
of
humans.
M.
tuberculosis
can
survive
and
thrive
within
infected
macrophages;
one
of
the
various
strategies
used
by
M.
tuberculosis
to
proliferate
within
the
phagosomes
of
immune
cells,
is
disrupting
the
membrane
trafficking
pathway.
Proteins
such
as
Rab
GTPases
are
required
for
phagosomes
to
mature
into
phagolysosomes.
M.
tuberculosis
can
inhibit
the
recruitment
of
several
Rab
GTPases
to
the
mycobacterial
phagosome,
includ-
ing
Rab
5
and
Rab
7,
thus
blocking
the
phagosome/lysosome
fusion
and
preventing
its
acidification
and
oxidation
[23].
Tuberculosis
patients
have
high
levels
of
oxidative
stress
markers
and
depletion
in
antioxidants
such
as
vitamin
C,
E,
and
glutathione
[24].
The
authors
of
a
recent
study
on
a

T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
103
tuberculosis
guinea
pig
model
reported
the
presence
of
oxida-
tive
stress
markers,
and
increased
oxidant-mediated
lung
and
spleen
lesions.
There
was
an
increase
in
Nrf2
expression
level
in
M.
tuberculosis-infected
cells,
but
Nrf2
was
mainly
localized
in
the
cytoplasm,
which
may
account
for
the
decreased
expression
levels
of
ARE-mediated
phase
II
enzymes
[25].
Human
infections
involving
rapidly
growing
mycobacteria
(RGM)
are
increasing
worldwide.
RGM
are
non-tuberculous
mycobacteria,
difficult
to
eradicate
because
of
their
high
level
of
resistance
and
because
they
occur
in
patients
with
weakened
immune
system.
RGM,
in
patients
with
a
pre-existing
condition
such
as
cystic
fibrosis
or
HIV,
is
a
factor
for
poor
clinical
out-
come.
Mycobacterium
abscessus,
an
RGM,
is
an
opportunistic
bacterium
with
two
phenotypes:
smooth
(S)
and
rough
(R).
The
R
phenotype
is
more
virulent
because
of
its
ability
to
induce
a
TLR2-dependent
hyper-inflammatory
response
from
the
host
innate
immune
system
[26].
M.
abscessus
is
abundantly
found
in
the
environment
and
causes
skin,
bone,
and
soft
tissue
infections;
it
has
been
increasingly
involved
in
the
exacerbation
of
lung
infections.
Currently,
its
high
level
of
resistance
to
antibiotics
is
a
great
limitation
for
treatment
that
may
account
for
the
likelihood
of
developing
chronic
airway
infections
and
an
increased
risk
of
death.
M.
abscessus,
like
M.
tuberculosis,
uses
the
host
immune
cells
as
a
reservoir
for
proliferation
and
seems
to
preferentially
grow
in
an
oxidative
environment.
Some
recent
in
vitro
experi-
ments
on
THP-1
derived
macrophages
proved
that
M.
abscessus
growth
was
enhanced
in
oxidative
conditions,
such
as
in
the
pres-
ence
of
oxygen
free
radicals,
but
was
inhibited
in
the
presence
of
MnTE-2-PyP
[27].
Oxidant
scavengers
such
as
MnTE-2-PyP
and
N-acetyl-L-cysteine
can
decrease
the
mycobacterial
load
in
M.
abscessus
infected
macrophages,
by
allowing
mycobacteria-
containing
phagosomes
to
mature
into
phagolysosomes,
thus
promoting
cell
survival
[28]
(Fig.
2).
Mycobacterial
infection
has
greatly
increased
recently,
with
the
higher
prevalence
of
immunodepressed
individuals.
Cur-
rently,
one
third
of
HIV
patients
are
carriers
of
M.
tuberculosis
and
this
population
has
a
greater
risk
of
developing
active
tuber-
culosis
disease
(WHO
global
tuberculosis
report
2012).
There
is
an
urgent
need
of
new
anti-mycobacterial
drugs
and
treatment
that
may
potentiate
the
current
drug
therapies.
6.
Nrf2
in
viral
infections
Viruses
can
invade
the
host
organism
through
many
routes
of
entry
but
the
most
frequent
are
infections
of
the
respiratory
sys-
tem
via
contaminated
aerosols.
Lung
epithelial
cells
and
alveolar
macrophages
are
then
the
primary
targets
of
the
viral
infection.
Most
viruses
are
rapidly
cleared
by
the
host
immune
defense
sys-
tem
but
some
including
herpes
virus,
hepatitis
virus,
and
HIV
can
cause
latent
or
recurrent
infections.
Encephalitis,
a
rare
condition
characterized
by
brain
inflam-
mation,
is
often
caused
by
viral
infections,
and
while
many
types
of
viruses
may
be
responsible
for
encephalitis,
the
most
severe
cases
are
associated
to
herpes
simplex
virus
type
1
(HSV-1).
Herpes
encephalitis,
if
not
treated,
can
lead
to
irreversible
neu-
rological
damage
or/and
death.
HSV-1
is
transmitted
by
direct
contact
and
dissemination
of
HSV-1
infection
is
facilitated
in
immunocompromised
individuals.
Chronic
exposure
to
HSV-1,
leading
to
persistent
inflammation
and
neuronal
damage,
may
be
a
potential
risk
factor
for
Alzheimer’s
disease
[29].
Very
little
is
known
about
the
role
of
Nrf2
in
HSV
infection;
but
the
authors
of
a
recent
study
on
HSV-infected
mice
demon-
strated
that
HSV
infection
activated
MAPK
signaling
pathway
induced
NADPH
oxidase-dependent
ROS
and
pro-inflammatory
cytokines
production
by
immune
cells.
Nevertheless,
the
antiox-
idant
HO-1
and
glutathione
peroxidase-1
response,
induced
by
oxidative
stress
through
activation
of
Nrf2,
was
insufficient
to
thwart
cell-death
and
tissue
damage
[30].
HIV
remains
a
major
public
health
concern
worldwide.
The
effectiveness
of
highly
active
antiretroviral
therapies
has
helped
increase
the
life
expectancy
of
HIV
patients,
a
factor
contributing
partly
to
the
constant
increase
of
HIV-infected
patients.
The
con-
sequence
of
improved
immune
function
in
HIV-infected
patients
is
the
increasing
incidence
of
cancers,
neurological
disorders,
and
secondary
infection-related
complications.
The
causes
are
still
unclear
but
several
authors
have
recently
stressed
the
role
of
oxidative
stress
in
the
pathogenesis
of
these
diseases
[31].
Many
HIV
patients
present
with
moderate
to
major
neurocogni-
tive
and/or
neuromotor
disorders
ranging
from
HIV
associated
neurocognitive
disorders
(HAND)
to
HIV
associated
dementia.
Hence,
the
exacerbation
of
chronic
oxidative
stress
conditions
worsens
the
HIV
associated
diseases,
increases
healthcare
costs,
morbidity,
and
mortality.
There
is
currently
no
effective
treat-
ment
available
for
these
neurological
complications.
The
first
authors
studying
HIV
reported
that
the
virus
pref-
erentially
infected
immune
cells
such
as
macrophages
and
monocytes
and
used
them
as
a
reservoir
for
viral
proliferation
and
dissemination.
HIV
patients
have
lower
expression
levels
of
antioxidants
than
non-infected
individuals.
The
enhanced
expression
of
Tat
and
gp120
viral
proteins
in
the
infected
host
cell
stimulates
the
production
of
ROS
and
the
depletion
of
glu-
tathione.
The
oxidative
condition
then
leads
to
cell
apoptosis
and
weakened
immune
defense
[32].
Chronic
oxidative
stress
in
HIV-infected
patients
may
facilitate
secondary
infections
by
opportunistic
pathogens,
a
condition
which
is
aggravated
by
alcohol
abuse.
Authors
study-
ing
HIV
transgenic
rats
reported
that
the
combination
of
alcohol
consumption
and
HIV
protein
gp120
significantly
increased
the
oxidative
damage
to
the
alveolar
epithelial
barrier
function,
and
this
far
more
than
with
alcohol
abuse
or
viral
infection
alone.
Alveolar
epithelial
cells
isolated
from
alcohol-treated
transgenic
rats
had
a
disruption
in
the
tight
epithelial
junctions
and
decreased
Nrf2
expression.
Treatment
with
the
glutathione
precursor
procystein
protected
the
epithelial
barrier
[33].
Hepatitis
is
an
inflammation
of
the
liver
caused
by
five
highly
pathogenic
viruses
(A,
B,
C,
D,
E).
Infection
by
hepatitis
B
or
C
virus
(HBV
and
HCV)
occurs
via
contaminated
blood
and
leads
to
chronic
hepatitis,
and
liver
cirrhosis.
Hepatitis
virus
is
the
leading
cause
of
hepatocellular
carcinoma
[34].
Chronic
inflammation
due
to
HBV
and
HCV
infections
generates
oxida-
tive
stress
but
also
induces
an
antioxidant
reaction,
although
the
role
of
these
infections
in
the
pathogenesis
of
hepatitis
infec-
tion
is
still
unclear.
Schaedler
et
al.
reported
an
induction
in
the
expression
of
Nrf2-regulated
cytoprotective
genes
by
HBV.

104
T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
Fig.
2.
The
pathogen’s
ability
to
resist
oxidative
environment
determines
its
survival.
La
capacité
du
pathogène
à
résister
à
un
environnement
oxydant
détermine
sa
survie.
They
suggested
that
an
increase
in
Nrf2-dependent
antioxidants
could
protect
HBV-infected
cells
from
oxidative-mediated
cell
damage
[35].
Ivanov
et
al.
also
recently
reported
that
HCV
strongly
induced
antioxidants
concomitantly
with
the
produc-
tion
of
ROS
[36].
Influenza
is
a
common
respiratory
disease
caused
by
three
types
of
RNA
viruses
(A,
B,
and
C),
that
causes
seasonal
flu
pandemics.
The
influenza
virus
is
easily
transmitted
via
aerosols
or
contaminated
surfaces
and
preferentially
targets
lungs.
Flu
symptoms
may
range
from
mild
viral
pneumonia
to
secondary
bacterial
pneumonia.
Several
authors
have
stressed
the
impor-
tance
of
Nrf2-activated
antioxidant
defense
systems
against
viral
infection.
Indeed,
the
overexpression
of
Nrf2,
in
alveo-
lar
epithelial
cells
and
macrophages
infected
with
influenza
A
virus,
helps
protect
cells
against
oxidant-mediated
cytotoxic-
ity
and
apoptosis
[37].
The
knock-down
of
Nrf2
expression
by
sh-RNA
was
inversely
correlated
with
the
sensitivity
of
human
nasal
epithelial
cells
to
influenza
A
virus
infection
[38].
Acute
respiratory
infections
are
a
major
cause
of
morbidity
world-
wide.
Influenza
virus
and
other
respiratory
viral
infections,
or
bacterial
infections
are
associated
with
chronic
obstructive
pul-
monary
disease
(COPD)
exacerbation.
COPD
may
be
related
to
risks
factors
such
as
chronic
cigarette
smoking,
outdoor
and
indoor
air
pollution,
occupational
dusts
and
chemicals.
COPD
is
characterized
by
airway
obstruction
due
to
the
narrowing
of
small
airways,
and
persistent
sputum
production,
resulting
in
the
slow
destruction
of
the
lung
parenchyma,
impaired
breath-
ing,
and
finally
death.
The
world
health
organization
(WHO)
predicts
that
COPD
may
become
the
third
leading
cause
of
death
worldwide
by
2030.
Nrf2
has
an
important
role
in
the
physiopathology
of
many
acute
and
chronic
respiratory
diseases
[39].
We
previously
described
a
substantial
decrease
in
Nrf2
expression
levels
with
an
increase
in
Nrf2
inhibitors,
Keap-
1
and
Bach-1
in
alveolar
macrophages
isolated
from
patients
with
cigarette
smoke-induced
lung
emphysema.
Sequestration
of
Nrf2
by
Keap-1/Bach-1
in
the
cytoplasm
prevented
its
translo-
cation
to
the
nucleus,
thus
resulting
in
an
increased
oxidative
burden
and
the
depletion
in
phase
II
enzymes
[40].
Yageta
et
al.
reported
that
cigarette
smoke
induced
antioxidants
in
wild-type
mice
but
failed
in
Nrf2−/−mice.
Moreover,
cigarette
smoke-
exposed
wild-type
mice
presented
a
higher
survival
rate
than
cigarette-exposed
Nrf2−/−mice,
after
influenza
A
virus
infec-
tion
[41].
7.
Nrf2
in
parasite
infection
Chagas
disease
is
caused
by
a
T.
cruzi
infection.
Patients
with
complications
of
Chagas
disease
present
with
cardiac,
nerve,
and
digestive
tissue
damage
due
to
inflammation/oxidative
stress-
induced
cell-death.
Macrophages
infected
by
T.
cruzi
trigger
an
oxidative
burst
that
seems
to
increase
macrophage
par-
asitism.
Mice
treated
with
several
Nrf2
inducers,
including
cobalt
protoporphyrin
(CoPP),
sulforaphane,
N-acetyl-cysteine,
or
pterostilbene,
had
a
decreased
T.
cruzi
inoculum.
The
inhibi-
tion
of
Nrf2
activity
with
SnPP
or
the
promotion
of
oxidative
stress
with
paraquat
or
H2O2treatment
increased
T.
cruzi
para-
sitism
[42].
Malaria
is
a
disease
caused
by
parasites
from
the
Plas-
modiidae
family
and
Plasmodium
falciparum
is
associated
with
most
fatal
outcomes.
The
severity
of
the
disease
is
correlated
with
excessive
inflammation
and
uncontrolled
parasite
prolif-
eration.
The
scavenger
receptor
CD36
specifically
identifies
Plasmodium-infected
erythrocytes.
CD36
is
transcriptionally
regulated
by
PPAR␥.
Macrophages
infected
by
P.
falciparum
had
a
decreased
CD36
expression
in
patients
with
malaria,
lead-
ing
to
a
decreased
CD36-mediated
phagocytosis
of
infected
erythrocytes.
It
should
be
noted
that
a
PPAR␥-independent
signaling
pathway,
controlled
by
Nrf2,
could
promote
the
expression
of
CD36.
PPAR␥−/−-macrophages
treated
with
Nrf2
inducers
and
infected
by
P.
falciparum
recovered
their
capacity
to
phagocytize
parasites,
a
significant
improvement
in
the
treat-
ment
of
malaria
[43].
All
this
suggests
Nrf2
inducers
could
be
used
as
a
therapy
in
infectious
diseases.

T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
105
8.
Nrf2:
a
promising
therapeutic
target
for
anti-infective
mechanism
Many
phytochemicals
and
synthetic
chemicals
have
been
successfully
used
to
enhance
the
antioxidant
system;
they
decrease
the
incidence
of
oxidative
stress-mediated
diseases.
Some
chemicals
extracted
from
plants,
reported
as
having
anti-infective,
antioxidant,
and
anti-inflammatory
properties,
are
Nrf2
signaling
inducers.
Astrocytes
and
neurons
pretreated
with
sulforaphane
(SFN),
a
natural
isothiocyanate
found
abun-
dantly
in
broccoli
sprouts,
were
able
to
resist
HSV-1
infection
by
producing
high
levels
of
antioxidant
enzymes
such
as
HO-1
and
glutathione
peroxidase
1,
decreasing
ROS-mediated
neurotoxicity
and
tissue
damage.
In
addition,
SFN
decreased
ROS
production
and
neuroinflammation
in
SFN-pretreated
mice
infected
with
HSV-1
[30].
Furthermore,
patients
with
COPD
pre-
sented
an
inhibition
of
the
Nrf2
signaling
pathway,
related
to
a
decreased
phagocytosis
of
macrophages.
SFN-treated
alveolar
macrophages
isolated
from
patients
with
COPD
were
infected
with
Haemophilus
influenza
and
Pseudomonas
aeruginosa.
The
cells
showed
restored
macrophage
phagocytosis
function
and
improved
bacterial
clearance
due
to
the
up-regulation
of
the
scavenger
MARCO
by
Nrf2
[44].
Activation
of
Nrf2
by
EGCG
(epigallocatechin-3-gallate),
a
green
tea-derived
polyphenol,
inhibited
the
replication
of
influenza
A
virus
and
significantly
decreased
ROS
level
in
infected
MDCK
cells.
EGCG-treated
mice
infected
with
influenza
A
virus
showed
a
decrease
in
virus
burden,
and
a
better
survival
rate
than
untreated
mice
[45].
Steinmann
et
al.
recently
reviewed
the
antiviral,
antibacterial,
and
antifungal
properties
of
EGCG
[46].
Kesic
et
al.
treated
human
nasal
epithelial
cells
with
SFN
or
EGCG.
They
reported
an
inverse
correlation
between
the
SFN-
or
EGCG-induced
expression
level
of
Nrf2
and
suscepti-
bility
to
viral
infection
[38].
Dimethyl
fumarate
(DMF;
also
found
as
BG-12
from
Biogen
Idec
Inc.)
is
an
oral
drug
used
for
several
chronic
and
inflamma-
tory
diseases
such
as
multiple
sclerosis,
psoriasis,
or
rheumatoid
arthritis.
BG-12
was
recently
used
in
phase
III
clinical
trials
to
effectively
delay
neuronal
degeneration
in
relapsing-remitting
multiple
sclerosis
[47].
The
potency
of
DMF
may
be
explained
by
its
inhibitory
effect
on
NF-␬B
signaling.
DMF
blocks
NF-
␬B
translocation
to
the
nucleus,
thus
preventing
a
production
of
pro-inflammatory
cytokines
[48].
Furthermore,
the
activation
of
Nrf2
by
DMF
stimulates
the
production
of
cytoprotective
enzymes
HO-1
and
NQO1
[49].
Albrecht
et
al.
demonstrated
that
low
concentrations
of
DMF
protected
neuronal
cells
from
oxida-
tive
stress-induced
apoptosis
by
Nrf2
activation,
and
increase
of
glutathione
production
[50].
Bardoxolone
methyl
is
a
synthetic
triterpenoid
used
to
reduce
inflammation
and
oxidative
stress
by
activation
of
the
Nrf2
signaling
pathway.
Bardoxolone
has
a
beneficial
effect
on
acute
ischemic
kidney
injury
by
up-regulating
Nrf2,
HO-
1,
and
PPAR␥
[51].
Bardoxolone-induced
Nrf2
in
colonic
epithelial
cells
resulted
in
beneficial
cell
protection
against
ionizing
radiation
[52].
The
recent
failure
of
bardoxolone
to
pass
phase
III
clinical
trial
due
to
its
numerous
adverse-
effects
suggests
that
a
greater
effort
should
be
made
in
finding
inducers
that
can
target
Nrf2
signaling
pathway
more
specifically
[53].
Other
small
molecule
activators
of
Nrf2
have
been
reported
as
good
candidates
for
the
treatment
of
oxidative
stress-
related
diseases.
N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-
trimethylphenoxy)
acetamide
could
induce
the
expression
of
ARE-dependent
enzymes
via
Nrf2
activation,
decrease
oxidant-
induced
cell-death,
and
act
on
decreasing
neurodegeneration
in
a
murine
model
for
amyotrophic
lateral
sclerosis
[54].
Another
ROS
scavenger
and
Nrf2
inducer,
N-acetyl-cysteine
(NAC)
was
used
to
treat
M.
tuberculosis-infected
Guinea
pigs,
resulting
in
a
decreased
mycobacterial
burden.
The
antioxidant
treatment
restored
the
antioxidant
balance
and
reduced
oxidant-mediated
cell
necrosis
in
lung
and
spleen
lesions
[25].
Similarly,
immor-
talized
brain
endothelial
cells
challenged
by
HIV-1
proteins
Tat
and
gp120
infections
had
an
increased
oxidative
stress
and
ROS
production.
This
was
not
the
case
in
cells
treated
with
NAC,
and
cell
apoptosis
was
reduced
[32].
Treatment
of
Nrf2−/−mice
with
NAC
improved
the
survival
rate
of
the
mice
when
challenged
by
a
lethal
dose
of
LPS,
inducing
septic
shock
[19].
9.
Conclusion
We
had
for
aim
to
highlight
the
major
role
of
antioxidants,
and
more
specifically
Nrf2,
in
the
innate
immune
system.
The
compiled
data
led
us
to
suggest
that
enhancing
expressions
of
antioxidants
to
decrease
oxidative
stress
generated
by
infection
may
help
protect
host
cells
from
oxidant-mediated
cytotoxicity
and
cell
apoptosis.
Combining
antioxidant
with
conventional
antibiotic
therapy
may
be
beneficial
in
the
prevention
and
the
treatment
of
many
infectious
diseases
with
oxidant-mediated
tissue
damage.
Hence,
activating
Nrf2
by
phytochemicals
or
synthetic
chemicals
may
be
of
considerable
interest
when
devel-
oping
new
therapeutic
strategies.
Disclosure
of
interest
The
authors
declare
that
they
have
no
conflicts
of
interest
concerning
this
article.
Acknowledgments
Marcel
Bonay
was
supported
by
the
Chancellerie
des
Univer-
sités
de
Paris
(Legs
Poix),
the
Fonds
de
Dotation
«
Recherche
en
Santé
Respiratoire
»,
and
the
«
Centre
d’Assistance
Respiratoire
à
Domicile
d’Île
de
France
(CARDIF)
».
References
[1]
Silva
MT.
When
two
is
better
than
one:
macrophages
and
neutrophils
work
in
concert
in
innate
immunity
as
complementary
and
cooperative
partners
of
a
myeloid
phagocyte
system.
J
Leukoc
Biol
2010;87(1):93–106.
[2]
Calkins
MJ,
Johnson
DA,
Townsend
JA,
Vargas
MR,
Dowell
JA,
Williamson
TP,
et
al.
The
Nrf2/ARE
pathway
as
a
potential
ther-
apeutic
target
in
neurodegenerative
disease.
Antioxid
Redox
Signal
2009;11(3):497–508.

106
T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
[3]
Touyz
RM.
Reactive
oxygen
species,
vascular
oxidative
stress,
and
redox
signaling
in
hypertension:
what
is
the
clinical
significance?
Hypertension
2004;44(3):248–52.
[4]
Van
Eeden
S,
Leipsic
J,
Paul
Man
SF,
Sin
DD.
The
relationship
between
lung
inflammation
and
cardiovascular
disease.
Am
J
Respir
Crit
Care
Med
2012;186(1):11–6.
[5]
Kregel
KC,
Zhang
HJ.
An
integrated
view
of
oxidative
stress
in
aging:
basic
mechanisms,
functional
effects,
and
pathological
considerations.
Am
J
Physiol
Regul
Integr
Comp
Physiol
2007;292(1):R18–36.
[6]
Kundu
JK,
Surh
YJ.
Emerging
avenues
linking
inflammation
and
cancer.
Free
Radic
Biol
Med
2012;52(9):2013–37.
[7]
Moi
P,
Chan
K,
Asunis
I,
Cao
A,
Kan
YW.
Isolation
of
NF-E2-related
factor
2
(Nrf2),
a
NF-E2-like
basic
leucine
zipper
transcriptional
activator
that
binds
to
the
tandem
NF-E2/AP1
repeat
of
the
beta-globin
locus
control
region.
Proc
Natl
Acad
Sci
U
S
A
1994;91(21):9926–30.
[8]
Cullinan
SB,
Gordan
JD,
Jin
J,
Harper
JW,
Diehl
JA.
The
Keap1-BTB
protein
is
an
adaptor
that
bridges
Nrf2
to
a
Cul3-based
E3
ligase:
oxida-
tive
stress
sensing
by
a
Cul3-Keap1
ligase.
Mol
Cell
Biol
2004;24(19):
8477–86.
[9]
Jin
Y,
Kim
HP,
Chi
M,
Ifedigbo
E,
Ryter
SW,
Choi
AM.
Deletion
of
caveolin-1
protects
against
oxidative
lung
injury
via
up-regulation
of
heme
oxygenase-1.
Am
J
Respir
Cell
Mol
Biol
2008;39(2):171–9.
[10]
Volonte
D,
Galbiati
F.
Inhibition
of
thioredoxin
reductase
1
by
cave-
olin
1
promotes
stress-induced
premature
senescence.
EMBO
Rep
2009;10(12):1334–40.
[11]
Li
W,
Liu
H,
Zhou
JS,
Cao
JF,
Zhou
XB,
Choi
AM,
et
al.
Caveolin-
1
inhibits
expression
of
antioxidant
enzymes
through
direct
interaction
with
nuclear
erythroid
2
p45-related
factor-2
(Nrf2).
J
Biol
Chem
2012;287(25):20922–30.
[12]
Kang
KW,
Lee
SJ,
Park
JW,
Kim
SG.
Phosphatidylinositol
3-kinase
regulates
nuclear
translocation
of
NF-E2-related
factor
2
through
actin
rearrangement
in
response
to
oxidative
stress.
Mol
Pharmacol
2002;62(5):1001–10.
[13]
Kimura
M,
Yamamoto
T,
Zhang
J,
Itoh
K,
Kyo
M,
Kamiya
T,
et
al.
Molec-
ular
basis
distinguishing
the
DNA
binding
profile
of
Nrf2-Maf
heterodimer
from
that
of
Maf
homodimer.
J
Biol
Chem
2007;282(46):33681–90.
[14]
Alam
J,
Stewart
D,
Touchard
C,
Boinapally
S,
Choi
AM,
Cook
JL.
Nrf2,
a
Cap’n’Collar
transcription
factor,
regulates
induction
of
the
heme
oxygenase-1
gene.
J
Biol
Chem
1999;274(37):26071–8.
[15]
Jain
AK,
Jaiswal
AK.
GSK-3beta
acts
upstream
of
Fyn
kinase
in
regulation
of
nuclear
export
and
degradation
of
NF-E2
related
factor
2.
J
Biol
Chem
2007;282(22):16502–10.
[16]
Rada
P,
Rojo
AI,
Chowdhry
S,
McMahon
M,
Hayes
JD,
Cuadrado
A.
SCF/{beta}-TrCP
promotes
glycogen
synthase
kinase
3-dependent
degra-
dation
of
the
Nrf2
transcription
factor
in
a
Keap1-independent
manner.
Mol
Cell
Biol
2011;31(6):1121–33.
[17]
Yu
S,
Khor
TO,
Cheung
KL,
Li
W,
Wu
TY,
Huang
Y,
et
al.
Nrf2
expression
is
regulated
by
epigenetic
mechanisms
in
prostate
cancer
of
TRAMP
mice.
PLoS
One
2010;5(1):e8579.
[18]
Arisawa
T,
Tahara
T,
Shibata
T,
Nagasaka
M,
Nakamura
M,
Kamiya
Y,
et
al.
The
relationship
between
Helicobacter
pylori
infection
and
pro-
moter
polymorphism
of
the
Nrf2
gene
in
chronic
gastritis.
Int
J
Mol
Med
2007;19(1):143–8.
[19]
Thimmulappa
RK,
Scollick
C,
Traore
K,
Yates
M,
Trush
MA,
Liby
KT,
et
al.
Nrf2-dependent
protection
from
LPS-induced
inflammatory
response
and
mortality
by
CDDO-Imidazolide.
Biochem
Biophys
Res
Commun
2006;351(4):883–9.
[20]
MacGarvey
NC,
Suliman
HB,
Bartz
RR,
Fu
P,
Withers
CM,
Welty-
Wolf
KE,
et
al.
Activation
of
mitochondrial
biogenesis
by
heme
oxygenase-1-mediated
NF-E2-related
factor-2
induction
rescues
mice
from
lethal
Staphylococcus
aureus
sepsis.
Am
J
Respir
Crit
Care
Med
2012;185(8):851–61.
[21]
Athale
J,
Ulrich
A,
Chou
Macgarvey
N,
Bartz
RR,
Welty-Wolf
KE,
Suliman
HB,
et
al.
Nrf2
promotes
alveolar
mitochondrial
biogenesis
and
resolution
of
lung
injury
in
Staphylococcus
aureus
pneumonia
in
mice.
Free
Radic
Biol
Med
2012;53(8):1584–94.
[22]
Hoetzenecker
W,
Echtenacher
B,
Guenova
E,
Hoetzenecker
K,
Woel-
bing
F,
Bruck
J,
et
al.
ROS-induced
ATF3
causes
susceptibility
to
secondary
infections
during
sepsis-associated
immunosuppression.
Nat
Med
2011;18(1):128–34.
[23]
Seto
S,
Tsujimura
K,
Koide
Y.
Rab
GTPases
regulating
phagosome
mat-
uration
are
differentially
recruited
to
mycobacterial
phagosomes.
Traffic
2011;12(4):407–20.
[24]
Vijayamalini
M,
Manoharan
S.
Lipid
peroxidation,
vitamins
C,
E
and
reduced
glutathione
levels
in
patients
with
pulmonary
tuberculosis.
Cell
Biochem
Funct
2004;22(1):19–22.
[25]
Palanisamy
GS,
Kirk
NM,
Ackart
DF,
Shanley
CA,
Orme
IM,
Basaraba
RJ.
Evidence
for
oxidative
stress
and
defective
antioxidant
response
in
guinea
pigs
with
tuberculosis.
PLoS
One
2011;6(10):e26254.
[26]
Roux
AL,
Ray
A,
Pawlik
A,
Medjahed
H,
Etienne
G,
Rottman
M,
et
al.
Overexpression
of
pro-inflammatory
TLR-2-signalling
lipoproteins
in
hypervirulent
mycobacterial
variants.
Cell
Microbiol
2011;13(5):692–704.
[27]
Oberley-Deegan
RE,
Rebits
BW,
Wea ver
MR,
Tollefson
AK,
Bai
X,
McGibney
M,
et
al.
An
oxidative
environment
promotes
growth
of
Mycobacterium
abscessus.
Free
Radic
Biol
Med
2010;49(11):
1666–73.
[28]
Oberley-Deegan
RE,
Lee
YM,
Morey
GE,
Cook
DM,
Chan
ED,
Crapo
JD.
The
antioxidant
mimetic
MnTE-2-PyP,
reduces
intracellular
growth
of
Mycobacterium
abscessus.
Am
J
Respir
Cell
Mol
Biol
2009;41(2):170–8.
[29]
Itzhaki
RF,
Lin
WR,
Shang
D,
Wilcock
GK,
Faragher
B,
Jamieson
GA.
Herpes
simplex
virus
type
1
in
brain
and
risk
of
Alzheimer’s
disease.
Lancet
1997;349(9047):241–4.
[30]
Schachtele
SJ,
Hu
S,
Lokensgard
JR.
Modulation
of
experimental
her-
pes
encephalitis-associated
neurotoxicity
through
sulforaphane
treatment.
PLoS
One
2012;7(4):e36216.
[31]
Sacktor
N,
Haughey
N,
Cutler
R,
Tamara
A,
Turchan
J,
Pardo
C,
et
al.
Novel
markers
of
oxidative
stress
in
actively
progressive
HIV
dementia.
J
Neuroimmunol
2004;157(1–2):176–84.
[32]
Price
TO,
Uras
F,
Banks
WA,
Ercal
N.
A
novel
antioxidant
N-acetylcysteine
amide
prevents
gp120-
and
Tat-induced
oxidative
stress
in
brain
endothelial
cells.
Exp
Neurol
2006;201(1):193–202.
[33]
Fan
X,
Joshi
PC,
Koval
M,
Guidot
DM.
Chronic
alcohol
ingestion
exacer-
bates
lung
epithelial
barrier
dysfunction
in
HIV-1
transgenic
rats.
Alcohol
Clin
Exp
Res
2011;35(10):1866–75.
[34]
Lupberger
J,
Hildt
E.
Hepatitis
B
virus-induced
oncogenesis.
World
J
Gas-
troenterol
2007;13(1):74–81.
[35]
Schaedler
S,
Krause
J,
Himmelsbach
K,
Carvajal-Yepes
M,
Lieder
F,
Klingel
K,
et
al.
Hepatitis
B
virus
induces
expression
of
antioxidant
response
element-regulated
genes
by
activation
of
Nrf2.
J
Biol
Chem
2010;285(52):41074–86.
[36]
Ivanov
AV,
Smirnova
OA,
Ivanova
ON,
Masalova
OV,
Kochetkov
SN,
Isaguliants
MG.
Hepatitis
C
virus
proteins
activate
NRF2/ARE
pathway
by
distinct
ROS-dependent
and
independent
mechanisms
in
HUH7
cells.
PLoS
One
2011;6(9):e24957.
[37]
Kosmider
B,
Messier
EM,
Janssen
WJ,
Nahreini
P,
Wang
J,
Hartshorn
KL,
et
al.
Nrf2
protects
human
alveolar
epithelial
cells
against
injury
induced
by
influenza
A
virus.
Respir
Res
2012;13(1):43.
[38]
Kesic
MJ,
Simmons
SO,
Bauer
R,
Jaspers
I.
Nrf2
expression
modifies
influenza
A
entry
and
replication
in
nasal
epithelial
cells.
Free
Radic
Biol
Med
2011;51(2):444–53.
[39]
Boutten
A,
Goven
D,
Artaud-Macari
E,
Boczkowski
J,
Bonay
M.
NRF2
tar-
geting:
a
promising
therapeutic
strategy
in
chronic
obstructive
pulmonary
disease.
Trends
Mol
Med
2011;17(7):363–71.
[40]
Goven
D,
Boutten
A,
Lecon-Malas
V,
Marchal-Somme
J,
Amara
N,
Crestani
B,
et
al.
Altered
Nrf2/Keap1-Bach1
equilibrium
in
pulmonary
emphysema.
Thorax
2008;63(10):916–24.
[41]
Yageta
Y,
Ishii
Y,
Morishima
Y,
Masuko
H,
Ano
S,
Yamadori
T,
et
al.
Role
of
Nrf2
in
host
defense
against
influenza
virus
in
cigarette
smoke-exposed
mice.
J
Virol
2011;85(10):4679–90.
[42]
Paiva
CN,
Feijo
DF,
Dutra
FF,
Carneiro
VC,
Freitas
GB,
Alves
LS,
et
al.
Oxidative
stress
fuels
Trypanosoma
cruzi
infection
in
mice.
J
Clin
Invest
2012;122(7):2531–42.
[43]
Olagnier
D,
Lavergne
RA,
Meunier
E,
Lefevre
L,
Dardenne
C,
Aubouy
A,
et
al.
Nrf2,
a
PPARgamma
alternative
pathway
to
promote
CD36
expres-
sion
on
inflammatory
macrophages:
implication
for
malaria.
PLoS
Pathog
2011;7(9):e1002254.

T.B.
Deramaudt
et
al.
/
Médecine
et
maladies
infectieuses
43
(2013)
100–107
107
[44]
Harvey
CJ,
Thimmulappa
RK,
Sethi
S,
Kong
X,
Yarmus
L,
Brown
RH,
et
al.
Targeting
Nrf2
signaling
improves
bacterial
clearance
by
alveolar
macrophages
in
patients
with
COPD
and
in
a
mouse
model.
Sci
Transl
Med
2011;3(78):78ra32.
[45]
Ling
JX,
Wei
F,
Li
N,
Li
JL,
Chen
LJ,
Liu
YY,
et
al.
Ameliora-
tion
of
influenza
virus-induced
reactive
oxygen
species
formation
by
epigallocatechin
gallate
derived
from
green
tea.
Acta
Pharmacol
Sin
2012;33(12):1533–41.
[46]
Steinmann
J,
Buer
J,
Pietschmann
T,
Steinmann
E.
Anti-infective
properties
of
Epigallocatechin-3-gallate
(EGCG),
a
component
of
Green
Tea.
Br
J
Pharmacol
2013;168(5):1059–73.
[47]
Kappos
L,
Gold
R,
Miller
DH,
Macmanus
DG,
Havrdova
E,
Limmroth
V,
et
al.
Efficacy
and
safety
of
oral
fumarate
in
patients
with
relapsing-
remitting
multiple
sclerosis:
a
multicentre,
randomised,
double-blind,
placebo-controlled
phase
IIb
study.
Lancet
2008;372(9648):1463–72.
[48]
Seidel
P,
Merfort
I,
Hughes
JM,
Oliver
BG,
Tamm
M,
Roth
M.
Dimethyl-
fumarate
inhibits
NF-{kappa}B
function
at
multiple
levels
to
limit
airway
smooth
muscle
cell
cytokine
secretion.
Am
J
Physiol
Lung
Cell
Mol
Physiol
2009;297(2):L326–39.
[49]
Linker
RA,
Lee
DH,
Ryan
S,
van
Dam
AM,
Conrad
R,
Bista
P,
et
al.
Fumaric
acid
esters
exert
neuroprotective
effects
in
neuroinflammation
via
activation
of
the
Nrf2
antioxidant
pathway.
Brain
2011;134(Pt
3):
678–92.
[50]
Albrecht
P,
Bouchachia
I,
Goebels
N,
Henke
N,
Hofstetter
HH,
Issberner
A,
et
al.
Effects
of
dimethyl
fumarate
on
neuroprotection
and
immunomod-
ulation.
J
Neuroinflammation
2012;9:163.
[51]
Wu
QQ,
Wang
Y,
Senitko
M,
Meyer
C,
Wigley
WC,
Ferguson
DA,
et
al.
Bardoxolone
methyl
(BARD)
ameliorates
ischemic
AKI
and
increases
expression
of
protective
genes
Nrf2
PPARgamma,
and
HO-1.
Am
J
Physiol
Renal
Physiol
2011;300(5):F1180–92.
[52]
Kim
SB,
Pandita
RK,
Eskiocak
U,
Ly
P,
Kaisani
A,
Kumar
R,
et
al.
Target-
ing
of
Nrf2
induces
DNA
damage
signaling
and
protects
colonic
epithelial
cells
from
ionizing
radiation.
Proc
Natl
Acad
Sci
USA
2012;109(43):
E2949–55.
[53]
Zhang
DD.
Bardoxolone
brings
Nrf2-based
therapies
to
light.
Antioxid
Redox
Signal
2012,
http://dx.doi.org/10.1089/ars.2012.5118.
[54]
Kanno
T,
Tanaka
K,
Yanagisawa
Y,
Yasutake
K,
Hadano
S,
Yoshii
F,
et
al.
A
novel
small
molecule
N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-
(2,4,6-trimethylphenoxy)
acetamide,
selectively
protects
against
oxidative
stress-induced
cell-death
by
activating
the
Nrf2-ARE
pathway:
Therapeutic
implications
for
ALS.
Free
Radic
Biol
Med
2012;53(11):2028–42.