Review
Decoding cell death signals in liver inflammation
Catherine Brenner1,2, , Lorenzo Galluzzi3,4,5, , Oliver Kepp3,6, Guido Kroemer4,5,6,7,8,⇑
1
INSERM, UMRS 769, LabEx LERMIT, F-92290 Châtenay Malabry, France; 2Université de Paris Sud/Paris VI, Faculté de Pharmacie, F-92290
Châtenay Malabry, France; 3Institut Gustave Roussy, F-94805 Villejuif, France; 4Université Paris Descartes/Paris V, Sorbonne Paris Cité,
F-75006 Paris, France; 5Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, F-75006 Paris, France;
6
INSERM, U848, F-94805 Villejuif, France; 7Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, F-94805 Villejuif, France;
8
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, F-75015 Paris, France
Summary
Inflammation can be either beneficial or detrimental to the liver,
depending on multiple factors. Mild (i.e., limited in intensity and
destined to resolve) inflammatory responses have indeed been
Keywords: Apoptosis; Lipotoxicity; Necrosis; Non-alcoholic necrosis steatohepatitis; Pattern recognition receptors; Tumor necrosis factor receptor.
⇑ Corresponding author. Address: INSERM, U848, Institut Gustave Roussy,
Pavillon de Recherche 1, 39 rue Camille Desmoulins, F-94805 Villejuif, France.
Tel.: +33 1 4211 6046; fax: +33 1 4211 6047.
E-mail address: [email protected] (G. Kroemer).
These authors contributed equally to this work.
Abbreviations: AGER, advanced glycosylation end product-specific receptor; ALOX5, arachidonate 5-lipoxygenase; ANT, adenine nucleotide translocase; ASK1,
apoptosis signal-regulating kinase 1; aSMase, acidic sphingomyelinase; ATF6,
activating transcription factor 6; CFLAR, caspase-8 and FADD-like apoptosis regulator; CHOP, C/EPB homologous protein; COX2, cyclooxygenase 2; CRT, calreticulin; DAMP, damage-associated molecular pattern; DAPK1, death-associated
protein kinase 1; DIABLO, direct IAP-binding protein with low pI; DCC, deleted in
colorectal carcinoma; eNOS, endothelial NOS; ERN1, endoplasmic reticulum to
nucleus signaling 1; Dwm, mitochondrial transmembrane potential; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EGFR, epidermal growth factor receptor; eIF2a, eukaryotic translation initiation factor 2a; EIF2AK3,
eIF2a kinase 3; EP, eosinophil peroxidase; ER, endoplasmic reticulum; FFA, free
fatty acid; FLAP, 5-lipoxygenase activating protein; FPR1, formyl peptide receptor
1; GADD34, growth arrest- and DNA damage-inducible gene 34; GM-CSF, granulocyte macrophage colony stimulating factor; GRP78, glucose-regulated protein,
78 kDa; GSK-3b, glycogen synthase kinase 3b; HBV, hepatitis B virus; HCV,
hepatitis C virus; HFD, high-fat diet; HMGB1, high mobility group box 1; HSC,
hepatic stellate cell; HSP, heat-shock protein; IFNc, interferon c; IL, interleukin;
IL-1RA, IL-1 receptor antagonist; iNOS, inducible NOS; IR, ischemia/reperfusion;
IRE1a, inositol-requiring enzyme 1a; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MAMP, microbe-associated molecular pattern; MBP, major basic protein; MLKL, mixed lineage kinase
domain-like; MOMP, mitochondrial outer membrane permeabilization; NK,
natural killer; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NO, nitric oxide; NOS, NO synthase; NOX, NADPH oxidase; NSAID,
non-steroidal anti-inflammatory drug; PERK, PKR-related ER kinase; PGAM5, phosphoglycerate mutase family member 5; PGE, prostaglandin E; PINK1, PTENinduced putative kinase 1; PP1, protein phosphatase 1; PRR, pattern recognition
receptor; PTGER1, PGE receptor 1, subtype EP1; PTPC, permeability transition
pore complex; ROS, reactive nitrogen species; RNS, reactive oxygen species; RIPK1, receptor-interacting protein kinase 1; S1P, sphingosine-1-phosphate; SIGLEC10, sialic acid-binding Ig-like lectin 10; SIRS, systemic inflammatory response
syndrome; STAT3, signal transducer and activator of transcription 3; TGFb, transforming growth factor b; TLR, Toll-like receptor; TNFa, tumor necrosis factor a;
TNFR1, TNF receptor 1; TRAIL, TNF-related apoptosis inducing ligand; VDAC,
voltage-dependent anion channel; UPR, unfolded protein response.
shown to exert consistent hepatoprotective effects, contributing
to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and
permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic
alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage,
fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer
cells, hepatic stellate cells, sinusoidal endothelial cells) and cells
that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including – but not limited to – cytokines,
chemokines, lipid messengers, and reactive oxygen species that
contribute to the apoptotic or necrotic demise of hepatocytes.
In turn, dying hepatocytes release damage-associated molecular
patterns that-upon binding to evolutionary conserved pattern
recognition receptors-activate cells of the innate immune system
to further stimulate inflammatory responses, hence establishing
a highly hepatotoxic feedforward cycle of inflammation and cell
death. In this review, we discuss the cellular and molecular
mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a
massive cell death response among hepatocytes.
Ó 2013 European Association for the Study of the Liver. Published
by Elsevier B.V. Open access under CC BY-NC-ND license.
Introduction
Hepatic inflammation, which accompanies the majority of acute
and chronic liver disorders, is a complex process that originates
in response to a variety of stress conditions [1]. As in most other
organs, hepatic inflammation is put in place to protect hepatocytes from injury, to favor the repair of tissue damage, and to promote the re-establishment of homeostasis, de facto exerting
consistent hepatoprotective effects. However, inflammatory
responses that are too intense or fail to resolve (i.e., they become
chronic) are near-to-invariably accompanied by a massive loss of
hepatocytes and hence cause an irreversible damage to the liver
parenchyma (Supplementary Discussion) [2]. As myofibroblasts
originating from hepatic stem cells take over and replace dead
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Review
hepatocytes, unresolved inflammation can stimulate a fibrotic/
cirrhotic response characterized by an irreversible decline in liver
functions [3]. Alternatively, owing to the fact that hepatocytes are
endowed with a consistent replicative potential and attempt at
reconstituting the dead parenchyma (which explains the clinical
success of the ‘‘split-liver’’ transplantation, in which two recipients received one half of the organ from a single donor) [4],
chronic inflammation significantly increases the risk for hepatic
carcinogenesis [5]. Besides these two end-stage conditions, dysregulated inflammatory responses have been associated with
most (if not all) hepatotoxic insults, including (i) ischemia/reperfusion (IR) injuries; (ii) alcohol overconsumption; (iii) intoxications by xenobiotics or heavy metals (e.g., Cu2+, Hg2+); (iv)
bacterial, viral and parasitic infections; as well as (v) systemic
metabolic conditions, such as non-alcoholic fatty liver disease
(NAFLD), non-alcoholic steatohepatitis (NASH), obesity, diabetes,
and the metabolic syndrome [6]. Importantly, many distinct
liver-resident cells, circulating cells that are specifically recruited
to the hepatic parenchyma in response to stress and a large panel
of bioactive molecules, encompassing cytokines, chemokines,
lipid messengers and highly diffusible pro-oxidants, have been
implicated in hepatic inflammation [1].
Key Points
•
While mild inflammatory responses are beneficial to
the liver as they favor the re-establishment of tissue
homeostasis, excessive or chronic inflammation not
only aggravates liver injury as triggered by a wide array
of hepatotoxic insults, but also promotes fibrosis and
hepatic carcinogenesis
•
When cell-intrinsic adaptive responses fail, hepatocytes
succumb to extracellular or intracellular stress
conditions by undergoing apoptosis, a geneticallycontrolled cell death mode that can be executed via
either of two signal transduction cascades, or necrosis,
which also can occur in a regulated fashion
•
Prominent signals leading to the massive demise of
hepatocytes include TNFα, the overgeneration of ROS,
as well as the accumulation of misfolded proteins
in the endoplasmic reticulum. All these stimuli also
mediate robust pro-inflammatory effects, for instance
by promoting the activation of NF-kB or the NLRP3
inflammasome
•
Multiple lipids including prostaglandins, leukotrienes,
ceramides, and free fatty acids have been involved in
the loss of liver parenchyma as induced by a plethora
of hepatotoxic stimuli. Lipotoxicity often proceeds
via stimulus-specific signaling pathways, yet almost
invariably is associated with inflammatory responses
•
Dying hepatocytes emit a wide array of DAMPs,
including ATP, HMGB1, and nuclear DNA, which de
facto link cell death to the elicitation and progressive
aggravation of a vicious hepatotoxic inflammatory
response. Hepatic inflammation is kept under control
by senescence, which is specifically perceived and
eliminated by NK cells, and autophagy, which limit the
production of ROS as well as the release of DAMPs
584
Most hepatic disorders are characterized by a profound mitochondrial dysfunction that can either drive the massive demise of
hepatocytes per se [7] or sensitize them to a variety of otherwise
non-lethal stress conditions, such as mild levels of hypoxia and/
or nutrient shortage [8]. Indeed, structural and functional alterations of mitochondria have been reported to accumulate in livers
affected by IR injury, NASH, sepsis and Wilson’s disease [8–10].
This reflects, on the one hand the central role of hepatocytes in
the systemic metabolism of carbohydrates and lipids as well as
in the detoxification of xenobiotics, and on the other hand the
critical functions of mitochondria at the hub of intracellular
metabolism, Ca2+ homeostasis, and cell death regulation [11].
Here we discuss the major deleterious consequence of liver
inflammation at the cellular level, that is the massive loss of functional hepatic parenchyma, focusing on the cellular and molecular players involved in the initiation of this phenomenon.
Cell death signals in the liver
Extrinsic and intrinsic apoptosis as well as regulated necrosis
(Fig. 1 and Supplementary Discussion) have been implicated in
the death of hepatocytes as triggered by a variety of hepatotoxic
insults such as viral and bacterial infections [12], metabolic disorders [13], alcohol overconsumption [14], and intoxication by
xenobiotics [15].
Extracellular signals
Members of the tumor necrosis factor (TNF) protein superfamily,
including TNFa, CD95L (also known as FASL) and TNF-related
apoptosis-inducing ligand (TRAIL, official name TNFSF10) are
among the most prominent and best characterized inducers of
hepatocyte death. TNFa is produced in massive amounts by
hematopoietic cells exposed in vivo to living bacteria or lipopolysaccharide (LPS), de facto accounting for the fatal shock syndrome
that develops in these conditions (which includes a prominent
hepatic component) [16]. Of note, both the fulminant hepatotoxic
effects and the systemic lethality of TNFa are consistently
decreased in Ripk3/ mice [17], suggesting that regulated necrosis may play an important role in this setting, which has long
been considered as a pure apoptotic model.
TNFa is a highly pleiotropic cytokine, inducing biological
effects as diverse as cell proliferation, metabolic activation,
inflammatory responses and (apoptotic or necrotic) cell death
[18]. Thus, ligand-bound TNR receptor 1 (TNFR1) can elicit distinct signal transduction cascades, depending on several factors.
Generally, the stabilization of TNFR1 trimers by TNFa is rapidly
connected to the production of reactive oxygen species (ROS)
(via the plasma membrane NAPDH oxidase NOX1 as well as by
mitochondrial and cytosolic sources) [19] and to the activation
of NF-jB, orchestrating a pro-survival and pro-inflammatory
response [20]. In this setting, the NF-jB-mediated transactivation
of caspase-8 and FADD-like apoptosis regulator (CFLAR, best
known as c-FLIP) blocks cell death signals at the level of TNFR1
[21], hence allowing for the secretion of several pro-inflammatory mediators including interleukin (IL)-6 and IL-8 [20]. Of note,
the acute phase protein IL-6 has been recently suggested to play a
prominent role in hepatic carcinogenesis as it activates signal
transducer and activator of transcription 3 (STAT3) [22]. Upon
internalization, the composition of the supramolecular complexes assembled around TNFR1 changes, generally allowing for
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Fig. 1. Molecular mechanisms of apoptosis. Extrinsic apoptosis can lead to
either ligation of death receptors (e.g., CD95) or drop in the concentration of
dependence receptor (e.g., PTCH1) ligands below a specific threshold. In
particular, CD95 ligand (CD95L) stabilizes CD95 trimers, hence allowing for the
assembly of a plasma membrane-associated supramolecular complex that favors
the proximity-induced activation of caspase-8. In turn, active caspase-8 sets off
the executioner machinery of apoptosis by activating a proteolytic cascade
involving caspase-3, -6, and -7. Conversely, PTCH1 appears to mediate the
activation of executioner caspases via caspase-9-dependent signal transduction
cascade. Several intracellular stress conditions (e.g., DNA damage) are specifically
sensed by small members of the BCL-2 protein family (BH3-only proteins), which
activate mitochondrial outer membrane permeabilization (MOMP) by stimulating
the pore-forming activity of BAX and BAK. Alternatively, MOMP can be initiated at
the inner mitochondrial membrane by the unspecific opening of the ‘‘permeability transition pore complex’’ (PTPC). Both these lethal cascades can be held in
check by anti-apoptotic BCL-2 proteins, which physically bind (hence inhibiting)
not only their pro-apoptotic counterparts but also various PTPC components.
MOMP is paralleled by the dissipation of the mitochondrial transmembrane
potential (Dwm) and results in the liberation of several mitochondrial proteins
such as cytochrome C (CYTC), which, together with the cytosolic adaptor APAF-1,
generates the caspase-9-activating platform known as ‘‘apoptosome’’; apoptosisinducing factor (AIF), which exerts caspase-independent pro-apoptotic functions
by mediating large-scale DNA fragmentation; and direct IAP-binding protein with
low pI (DIABLO), which physically antagonizes various inhibitor of apoptosis
proteins (IAPs). Thus, MOMP activates both caspase-dependent and caspaseindependent mechanisms of apoptosis. Of note, the caspase-8-mediated cleavage
of the BH3-only protein BID constitutes a major link between the extrinsic and
intrinsic apoptotic pathways. tBID, truncated BID.
the recruitment and proximity-induced activation of caspase-8
[23]. In this setting, caspase-8 inactivates receptor-interacting
protein kinase 1 (RIPK1) and RIPK3 [24] while setting off the
apoptotic caspase cascade, either alone or sustained by a mitochondrial amplification loop mediated by truncated BID [25].
Conversely, in caspase-8-deficient scenarios (e.g., in Casp8 knockout models or in the presence of caspase inhibitors), RIPK1 and
RIPK3 engage in physical interactions to form the ‘‘necrosome’’,
the signaling entity that leads to necroptosis [24] (Fig. 2).
Both Casp3/ and Bid/ mice are more resistant to lethal
hepatitis as triggered by anti-FAS agonistic antibodies than their
wild type littermates [26,27], suggesting that executioner caspas-
Fig. 2. Tumor necrosis factor signaling. Similar to CD95 ligand, tumor necrosis
factor a (TNFa) stabilizes pre-assembled TNFa receptor 1 (TNFR1) trimers, hence
allowing for the assembly of a membrane-proximal supramolecular complex
including (but not limited to) TRADD, FADD, receptor-interacting protein kinase 1
(RIPK1), as well as multiple cellular inhibitors of apoptosis proteins (cIAPs). In this
setting, RIPK1 gets rapidly ubiquitylated (by cIAPs and other ubiquitin ligases)
and hence triggers a signal transduction cascade that leads to the activation of
NF-jB, in turn resulting in the production of anti-apoptotic and pro-inflammatory
factors. Conversely, upon deubiquitylation (by cylindromatosis [CYLD] and other
enzymes), RIPK1 can recruit either caspase-8, therefore setting off the apoptotic
caspase cascade (see also Fig. 1), or, in caspase-incompetent settings, its homolog
RIPK3, resulting in the assembly of the ‘‘necrosome’’. In this latter case, both
RIPK1 and RIPK3 become phosphorylated and activate a mixed lineage kinase
domain-like (MLKL)-, phosphoglycerate mutase family member 5 (PGAM5)-,
mitochondrial fragmentation-dependent signaling pathway leading to necrosis.
CFLAR, caspase-8 and FADD-like apoptosis regulator; DRP1, dynamin-related
protein 1; IjB, inhibitor of NF-jB; IKK, IjB kinase; IL, interleukin; TAB, TAK1binding protein; TAK1, transforming growth factor b (TGFb)-associated kinase 1;
Ub, ubiquitin.
es and mitochondrial outer membrane permeabilization (MOMP)
are equally critical for the death of hepatocytes in this model.
Mice lacking mitogen-activated protein kinase 9 (Mapk9), best
known as c-JUN N-terminal kinase 2 (JNK2) are protected from
D-galactosamine/LPS- or D-galactosamine/TNFa-induced hepatotoxicity [28], perhaps owing to a phosphorylation-dependent stabilization of the anti-apoptotic protein MCL1 [28,29]. Along
similar lines, JNK1 has been shown to be required for TNFainduced fulminant hepatitis in vivo as it stimulates the ITCHdependent targeting of c-FLIP to proteasomal degradation [30].
Thus, distinct JNK isoforms, which can be directly activated upon
recruitment to the signaling complex assembled at the intracellular tails of TNFR1 or respond to ROS [19], play an important role
in the lethal signaling cascades triggered by TNFa and other hepatotoxic conditions (e.g., acetaminophen intoxication) [31].
Intracellular signals
As the liver is often exposed to biological and chemical stimuli
(see above), hepatocytes must rely on robust adaptive responses
for the maintenance of cellular and histological homeostasis. Key
processes in this context are the endoplasmic reticulum (ER)
stress response, autophagy, and the response to redox stress.
ER stress and autophagy: The intraluminal accumulation of
misfolded proteins significantly affects ER functions, including
the regulation of Ca2+ homeostasis, and generally results in the
activation of a multipronged adaptive mechanism known as
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unfolded-protein response (UPR) [32]. In mammalian cells, the
UPR is elicited by three distinct sensors: endoplasmic reticulum
to nucleus signaling 1 (ERN1, best known as inositol-requiring
enzyme 1a [IRE1a]), activating transcription factor 6 (ATF6)
and eukaryotic translation initiation factor 2a (eIF2a) kinase 3
(EIF2AK3, best known as PKR-related ER kinase [PERK]) [32].
Under physiological conditions, IRE1a, ATF6, and PERK engage
in inhibitory interactions with the ER-resident chaperone glucose-regulated protein, 78 kDa (GRP78). Conversely, accumulating unfolded proteins competitively displace GRP78 from IRE1a,
ATF6 and PERK, leading to their activation and eventually to
the upregulation of mechanisms that attempt to re-establish
homeostasis, mainly involving (i) a general (but not complete)
translational arrest, (ii) the upregulation of factors that promote
protein folding and degradation, and (iii) the activation of
autophagy [32]. Autophagy is a homeostatic mechanism that is
critical both in baseline conditions, for the maintenance of intracellular homeostasis [33], and during adaptive stress responses,
when it exerts major cytoprotective functions [34].
When the ER stress is mild and/or temporary, the combined
activation of the UPR and autophagy generally allows for the
recovery of homeostasis [35]. Conversely, protracted and/or
excessive signaling via ER stress sensors is associated with the
initiation of a mitochondrial pathway of apoptosis that involves,
among other proteins, the transcription factor C/EPB homologous
protein (CHOP), the protein phosphatase 1 (PP1) activator growth
arrest- and DNA damage-inducible gene 34 (GADD34), apoptosis
signal-regulating kinase 1 (ASK1), and JNK [36]. Interestingly, at
least part of the effects of JNK and ASK1 stem from their ability
to phosphorylate anti-apoptotic members of the BCL-2 family
[37], hence de-inhibiting Ca2+-modulatory (e.g., inositol 1,4,5trisphosphate receptor) [38], pro-autophagic (e.g., Beclin 1) [39]
and pro-apoptotic (e.g., BAX, BAK) factors [40]. Thus, JNK and
ASK1 appear to regulate a complex crosstalk between mechanisms for the maintenance of intracellular homeostasis (such as
ER stress and autophagy) and the adaptive organismal response
for the removal of irremediably compromised, and hence potentially dangerous cells (apoptosis).
A causal link between ER stress responses and the apoptotic
demise of hepatocytes has been established in a wide panel of
hepatic disorders, including viral infections [41], intoxication
with bacterial toxins [42], IR injuries [43], transplantation [44],
NASH and NAFLD [45]. Of note, the ER stress response is required
for the perception of cell death as immunogenic [46], and (no less
than) three distinct ER-resident chaperones, namely, calreticulin
(CRT), ERp57 and GP96, have been shown to exert immunostimulatory effects [47,48]. It is therefore tempting to speculate, yet
remains to be formally demonstrated, that ER stress inhibitors
may be useful for preventing the unwarranted rejection of liver
allografts.
ROS: ROS, including anion peroxide and hydrogen peroxide,
are a normal side product of the mitochondrial respiratory chain
(mainly produced cat complex I and III), and, as they constitute
highly reactive and highly diffusible species, are involved in several signal transduction cascades and adaptive stress responses
[11]. A quantitatively minor but functionally not less important
fraction of intracellular ROS is produced by plasma membrane,
cytosolic and reticular multicomponent NADPH oxidases (NOXs),
including NOX1, which participates in TNFR1-dependent NF-jB
activation, JNK activation, and necroptosis [49], by xanthine oxidase, which catalyzes one step of purine catabolism [50], and by
586
enzymes of the cytochrome P450 family [51]. In the liver, the latter appear to account for a consistent proportion (if not for the
majority) of intracellular ROS production, even in the absence
of cytochrome P450 substrates [52].
In physiological settings, the cytotoxic potential of ROS is held
in check by a diversified battery of mitochondrial, cytosolic, and
peroxisomal antioxidant systems, including superoxide dismutases, catalases, peroxiredoxins, thioredoxin, glutathione and
thiol-containing proteins [11]. In response to multiple stimuli,
however, ROS levels exceed the buffer capacity of these systems,
resulting first in the activation of an adaptive response aimed at
the re-establishment of redox homeostasis coupled to an inflammatory response [53], and then in intracellular damage, progressive mitochondrial dysfunction (paralleling the oxidation of
respiratory complexes and several other proteins involved in
mitochondrial metabolism), and cell death [7]. In particular,
intracellular ROS are known to affect the functions of key components of the permeability transition pore complex (PTPC) including voltage-dependent anion channel 1 (VDAC1) [54], adenine
nucleotide translocases (ANTs) [55] and subunits of the F1FO ATPase [56], hence stimulating PTPC opening, MOMP and cell death
via intrinsic apoptosis. Of note, in some cell types including hepatocytes, ROS activate ASK1 and their cytotoxic potential is largely
determined by its subcellular localization and interacting partners [57].
The implication of ROS in the death of hepatocytes exposed to
toxic insults has been extensively documented, in vitro and
in vivo. Thus, redox stress has been shown to constitute an etiological determinant of hepatotoxicity during IR [58,59], viral
infection [60], endotoxemia [61] ethanol intoxication [62] and
NASH [63], to mention a few examples. Conversely, ROS appear
to protect cirrhotic hepatocytes from transforming growth factor
b (TGFb)-induced apoptosis [64], and to be (at least partially)
responsible for the beneficial effects of (hepatic) ischemic preconditioning on hepatic and renal IR [65,66]. Finally, even in
the absence of overt cell death, ROS-dependent alterations of
mitochondrial metabolism in the liver have been associated with
multiple metabolic conditions, including insulin resistance [67].
NO and RNS: Similar to ROS, nitric oxide (NO) and reactive
nitrogen species (RNS) exert a large spectrum of biological effects
including (but not limited to) the stimulation of cell growth and
tissue regeneration, the control of vascular functions, and the
induction of cell death [68]. The major intracellular source of
NO is represented by NO synthases (NOS), which catalyze the
NAPDH- and O2-assisted conversion of L-arginine into citrulline
and NO [69]. However, whereas the endothelial NOS (eNOS) is
constitutively active and mainly mediates the beneficial effects
of NO on vasculature, its inducible counterpart (iNOS) is upregulated in response to stress, catalyzing intense (and hence potentially dangerous) waves of NO production [69]. At the cellular
level, excess NO and RNS resemble ROS in their capacity to impair
energetic metabolism as they covalently modify a large panel of
proteins including mitochondrial complex IV [70] and ANT [71]
(both involved in mitochondrial respiration) as well as glyceraldehyde-3-phosphate dehydrogenase (GAPH) (a glycolytic
enzyme) [72], hence favoring the opening of the PTPC and cell
death.
In line with these considerations, NO and RNS have been
ascribed both hepatoprotective and hepatotoxic effects. For
instance, NO has been suggested to participate in liver
regeneration [73] and to protect hepatocytes from cell death at
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JOURNAL OF HEPATOLOGY
reperfusion [74], but also to account (at least in part) for the
failure of steatotic livers to engraft [75] and to contribute to
NASH [76].
The case of IR injury
IR is a biphasic process entailing a massive necrotic and apoptotic
cell death response that is initiated at reperfusion, along with the
most often unsuccessful attempt of cells to re-establish homeostasis via autophagy [77] Hepatic IR is a particularly interesting
model as its main pathological consequence, i.e., the massive loss
of hepatocytes during reperfusion, originates from a complex
crosstalk between ER stress, oxidative stress, and inflammation
during ischemia. Hypoxia induces indeed a considerable overgeneration of ROS [78], in turn (i) directly stimulating the (at least
partially) NF-jB-dependent transactivation of various proinflammatory mediators [53] and (ii) promoting protein unfolding and hence triggering the ER stress response (as documented
by the activation of XBP1 and ATF6 in the parenchyma of livers
undergoing IR) [44,45]. Interestingly, the hepatic ER stress
response per se exerts pro-inflammatory functions, both as it
allows for the activation of the pro-inflammatory hepatocytespecific transcription factor CREBH [79] and as it sensitizes
liver-resident macrophages to stimulation by Toll-like receptor
4 (TLR4) agonists as well as hepatocytes to cell death induction
by TNFa [44]. In line with this notion, mice pretreated with 4phenylbutyrate, a synthetic chaperone used as an ER stress inhibitor, were protected from hepatic IR while manifesting reduced
pro-inflammatory responses [80]. Moreover, ischemic pre-conditioning has been associated with the upregulation of the IL-1
receptor antagonist IL-1RA, BCL-2 and NO [81], suggesting that
the hepatoprotective effects of this maneuver stem from the inhibition of inflammation and cell death coupled to the activation of
repair mechanisms. Of note, TLR4 agonists, which generally operate as adjuvants to promote immune responses, have been shown
to reduce hepatic damage in steatotic livers maintained in UW
preservation solution [82], implying that TLR4 signaling not
always mediates hepatotoxic effects.
Taken together, these observations suggest that the hepatotoxic effects of IR originate from a complex crosstalk between
hepatocytes, tissue-resident immune cells and immune cells that
are recruited to the site of injury. In this setting, a major role is
played by the ER stress response, by lipid signals and by damage-associated molecular patterns (DAMPs) that are released by
dying hepatocytes, as discussed below.
Prostaglandins
Cyclooxygenase 2 (COX2)-derived prostaglandins have been
implicated in diverse physiopathological processes including cell
proliferation and activation of inflammatory responses [84]. Most
non-steroidal anti-inflammatory drugs (NSAIDs), including blockbusters such as acetylsalicylic acid, ibuprofene and sulindac, de
facto operate as relatively unspecific COX inhibitors, blocking
the conversion of arachidonic acid into prostaglandins [84]. As
it stands, the implication of COX2 in hepatic diseases remains
controversial. On the one hand, indeed, the hepatocyte-specific
transgenic expression of COX2 has been shown to accelerate Dgalactosamine/LPS-induced liver failure by a prostaglandin E
(PGE) receptor 1, subtype EP1 (PTGER1)-dependent mechanism
involving the activation of JNK2 [85], and PGE2 has been causally
involved in NAFLD and NASH [86]. On the other hand, robust
genetic data indicate that COX2 protects mice from fatal hepatitis
as triggered by agonistic anti-FAS antibodies, presumably as it
regulates the expression of the epidermal growth factor receptor
(EGFR) [87]. Along similar lines, prostaglandins (and in particular
PGE2) appear to mediate robust hepatoprotective functions
against IR and acetaminophen hepatotoxicity [88,89].
Leukotrienes
Together with prostaglandins, leukotrienes, which are generated
by the catalytic activity of the enzyme arachidonate 5-lipoxygenase (ALOX5), constitute the major products of arachidonic acid
metabolism [90]. Besides participating in inflammatory
responses, leukotrienes promote chemotaxis and regulate the
contraction of tracheal smooth muscles, contributing to the pathogenesis of asthma [91]. The knockout of Alox5 reportedly ameliorates the steatotic, inflammatory, and fibrotic responses
spontaneously developing in Apoe-/- mice [92] or resulting from
the administration of CCl4 [93]. Along similar lines, chemical
inhibitors of ALOX5 or 5-lipoxygenase-activating protein (FLAP,
an ALOX5 interactor) have been shown to reduce CCl4-induced
liver injury [94] and to limit the inflammatory infiltration of
the hepatic parenchyma in several distinct models of NASH and
NAFLD [92], perhaps as they induce the preferential demise of
activated Kupffer cells. Similar to ALOX5, arachidonate 15-lipoxygenase, another enzyme involved in arachidonic acid metabolism,
may also play a prominent role in the pathogenesis of NASH and
NAFLD [95].
Ceramides
Lipids, major pleiotropic signals of inflammation and cell
death
Lipids constitute a structurally heterogeneous group of hydrophobic molecules that serve a wide variety of functions. Lipids
are indeed prominent energy-storing molecules (leading to a
much higher caloric yield, i.e., 9 kcal/g, than carbohydrates
and proteins, i.e., 4 kcal/g), critically contribute to the formation
of biological membranes, and participate in several signal transduction cascades [83]. The liver plays a central role in the systemic metabolism of lipids and several classes of lipids,
including (but not limited to) prostaglandins, leukotrienes, ceramides and fatty acids, have been shown to mediate hepatotoxic
effects while stimulating hepatic inflammation.
Ceramides are lipid messengers that accumulate in response to
various stress conditions, either upon the hydrolysis of sphingomyelin by sphingomyelinases or via a 3-step biosynthetic pathway that mainly occurs at ER membranes [96]. Ceramides are
well known for their capacity to control proliferation and apoptosis at a cell-autonomous level [97] and are now emerging as
prominent regulators of systemic metabolism [96]. In particular,
ceramides, which also accumulate in response to death receptor
activation [98], promote direct mitochondriotoxic effects [99],
stimulate ROS generation [100], and inhibit various anti-apoptotic signal transducers, including AKT [101]. Mice lacking acidic
sphingomyelinase (aSMase) are significantly protected against
the lethal hepatotoxic effects of D-galactosamine/LPS, TNFa and
agonistic anti-FAS antibodies [102,103]; and imipramine, a chem-
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587
Review
ical aSMase inhibitor, has been shown to limit hepatic damage
upon IR injury [104]. Along similar lines, myriocin, an inhibitor
of de novo ceramide synthesis, appears to reduce body weight,
enhances metabolism and ameliorates energy expenditure in
genetically obese (ob/ob) mice as well as in animals exposed to
a high-fat diet (HFD) [105]. Of note, myriocin has also been
reported to suppress hepatitis C virus replication (HCV) in vivo
[106], suggesting that ceramides may constitute central hepatotoxic mediators in a wide variety of pathological settings.
that the stage of disease correlates with increased p53 expression
levels and decreased amounts of BCL-2 [119]. Taking this into
account, it would be an oversimplification to consider all lipids
as equally hepatotoxic. Indeed, while the lipotoxic potential of
FFAs taken as a single class of lipids is established, (i) distinct FFAs
differ in their ability to promote cell death, saturated and long lipids being generally viewed as more toxic than their non-saturated
and short counterparts [119]; and (ii) neutral fats (in particular
triglycerides) appear to be relatively inert, if not to activate an
adaptive response that exerts hepatoprotective effects [109,120].
Fatty acids and neutral fats
Fatty acids and neutral fats (including mono-, di-, and triglycerides) constitute prominent energetic substrates, central components of cell membranes and serve as precursors for the
synthesis of several other molecules [83]. Nevertheless, the accumulation of fatty acids and neutral fats as a result of metabolic
disorders (e.g., insulin resistance, which is generally accompanied
by an increase in circulating fatty acids) or an unbalanced diet is
toxic for several tissues, including the liver [107]. In these settings, as well as in response to various toxins and xenobiotics
including ethanol, fatty acids and neutral fats (mainly di- and triglycerides) accumulate within hepatocytes, resulting in a peculiar
alteration of the hepatic parenchyma known as steatosis [107].
Irrespective of its origin, steatosis is associated with (at least
some extent) of hepatic damage, resulting from the pro-apoptotic
activity of free fatty acids (FFAs) and (hepatocyte death-related)
inflammation [108].
Results from recent studies involving leptin- (ob/ob) and leptin receptor-deficient (db/db) obese mice and multiple in vitro
models of lipotoxicity [109,110] suggest that the hepatotoxic
effects of FFAs are mediated in part by mitochondrial apoptosis
and in part by death receptor-transduced signals, but not by
RIPK1-dependent signal pathways. In particular, FFA-induced
apoptosis appears to involve the activation of the tumor suppressor protein p53 [111], the overexpression of TRAIL receptors
[111], ROS overproduction [112], BAX-dependent lysosomal
membrane permeabilization [113], as well as direct mitochondriotoxic effects that result from the local accumulation of modified lipids, such as oxidized cardiolipin [114] and ceramides
[115]. In line with this notion, a combination of saturated fatty
acids such as palmitic and oleic acid has been shown to sensitize
hepatocytes to cell death induction by various stimuli [9]. In ob/
ob mice, this manifests with morphological and structural alterations of hepatocyte mitochondria as well as with reduced levels
of VDAC1 phosphorylation by glycogen synthase kinase 3b
(GSK-3b), increasing the propensity of these organelles to accumulate Ca2+ ions and to undergo lethal MOMP [9]. This said,
the actual role of GSK-3b in lipotoxicity (i.e., whether it promotes
or inhibits FFA-induced cell death) remains to be clarified, as contrasting observations have been reported in this respect [9,116].
The liver of HFD-fed mice is infiltrated by a consistent amount
of immature myeloid cells. Together with liver-resident Kupffer
cells [117], these CD11b+Ly6ChighLy6G cells secrete TH1 cytokines such as IL-12 and interferon c (IFNc), hence facilitating
the activation-induced death of local natural killer T (NKT) cells
and initiating a vicious feedforward loop bridging inflammation
and HFD-associated hepatotoxicity [118]. The existence of a physiopathologically relevant link between FAAs, apoptosis, and
inflammation has been validated by an immunohistochemical
study of hepatic biopsies from 84 NAFLD patients, demonstrating
588
DAMPs, amplification signals for inflammation and cell death
DAMPs, also called alarmins, constitute a group of chemically
heterogeneous molecules that are exposed/released by dying
cells to operate as modulators (most often activators) of sterile
inflammation [121] (Table 1). Of note, in physiological conditions,
DAMPs serve ‘‘daily jobs’’, i.e., they contribute to inflammationunrelated cellular functions, in thus far resembling several components of the cell death machinery [122].
To date, molecules as diverse as nuclear and mitochondrial
DNA [123–126], purine nucleotides (i.e., ATP, UTP) [127,128], uric
acid [129,130], lipids (i.e., sphingosine-1-phosphate [SP1]) [131],
nuclear factors (i.e., high-mobility group box 1 [HMGB1], IL-33)
[124,132,133], mitochondrial N-formyl peptides [121,126], ER
chaperones (i.e., CRT, ERp57, GP96) [47,48], heat-shock proteins
(HSPs, e.g., HSPA1A, HSP90AA1) [48,134–136] cytoskeletal proteins (i.e., F-actin) [137] and S100 proteins [138] have been found
to behave as DAMPs. In spite of such a structural and chemical
heterogeneity, DAMPs share the property of being concealed
from the microenvironment in physiological conditions and of
being exposed and/or released in response to cellular damage
[139]. Until recently, necrotic cells were considered as the most
prominent, if not the only, source of DAMPs [139]. At least in part,
this notion stemmed from the facts that the plasma membrane
remains intact throughout apoptosis and that apoptotic corpses
are normally cleared by phagocytes before secondary necrosis
intervenes (and hence before their content can passively spill into
the extracellular microenvironment), owing to the exposure of
specific eat-me signals such as phosphatidylserine [140]. However, it is now clear that apoptosis can also be associated with
the exposure/release of several DAMPs and hence can activate
inflammatory or immune responses [46].
Interestingly, DAMPs may not always operate as pro-inflammatory mediators. For instance, IL-33, a cytokine that in healthy
cells mainly functions as a transcription factor [133], appears to
inhibit, rather than stimulate, inflammatory reactions elicited
by dying cells, perhaps owing to its capacity of preferentially activating TH2 immune responses [141]. Moreover, the binding of
generally pro-inflammatory DAMPs, such as HMGB1 and HSPs,
to ‘‘alternative’’ receptors, such as CD24 or SIGLEC10, sialic
acid-binding Ig-like lectin 10 (SIGLEC10), has been reported to
mediate consistent anti-inflammatory effects [134].
The implication of specific DAMPs and cognate pattern recognition receptors (PRRs) in the pathogenesis of liver diseases has
just begun to emerge. Thus, hepatocytes have been shown to
secrete ATP, most likely via pannexin 1 channels, as they succumb to FFAs [142] and acetaminophen [143], promoting the
P2Y2-dependent infiltration of neutrophils and hence aggravating hepatic damage [143]. The non-histone chromatin-binding
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JOURNAL OF HEPATOLOGY
Table 1. Examples of DAMPs potentially involved in liver disease.
DAMP
ATP
UTP
CRT
ERp57
F-actin
HMGB1
HSPs
IL-33
mtDNA
nDNA
N-formyl
peptides
S100
proteins
S1P
Uric acid
Function(s)
Purine metabolites
NLRP3 inflammasome
activators
ER chaperones
Eat-me signals
Cytoskeletal component
DC recruitment
Multifunctional
nuclear factor
Adjuvant
Anti-inflammatory
function (?)
Molecular chaperons
Adjuvants
Anti-inflammatory
function (?)
Repressor of nuclear
transcription
Anti-inflammatory factor
Gene expression
Adjuvant
NLRP3 inflammasome
activation
Gene expression
Adjuvant
NLRP3 inflammasome
activator
Pro-fibrotic molecule
Mitochondrial polypeptides
Potent neutrophil
activators
Pleiotropic roles
Adjuvants
Receptor(s) Emission pathway
P2RX7
Secreted via autophagyP2Y2
and PANX1-dependent
mechanisms
CD91
Exposed upon ER stress via
the Golgi secretory pathway
CLEC9a
Exposed upon PMP
Lipid
Anti-apoptotic stimulus
Come and get me-signal
Purine catabolite
Pro-inflammatory
metabolite
S1PR
Notes
Involved in the pathogenesis of
conA-induced acute liver injury
Ref.
[127, 128,
143]
ER stress plays a causative role
in several hepatic disorders
Not yet formally involved
in liver disease
Involved in the pathogenesis
of acute liver failure,
hepatic IR and HBV infection
[46, 47]
[137]
AGER
TLR4
CD24/
SIGLEC10
Released upon
NMP and PMP
TLR2
TLR4
Released upon PMP
or secreted via active,
exosome-dependent routes
Implicated in the response
to hepatic IR and other
hepatotoxic conditions
[48, 134-136]
IL1RL1
Released upon
NMP and PMP
[133, 158,
159]
NLRP3
TLR9
Released upon mitochondrial
damage and PMP
Released during acute and
chronic liver failure, hepatic
IR and conA intoxication
mtDNA can be detected
in the circulation of patients
undergoing acute liver failure
NLRP3
TLR9
Released upon
NMP and PMP
Implicated in the fibrotic
response to acetaminophen
[123, 124,
150]
FPR1
Released upon mitochondrial
damage and PMP
[121, 126,
152]
AGER
TLR4
Secreted via conventional
secretory pathways or
released upon PMP
Secreted via a carrierdependent mechanism or
released upon PMP
Released upon PMP
N-formyl peptides can be
detected in the blood of patients
undergoing acute liver failure
Not yet formally involved
in liver disease, participate in
hepatocellular carcinogenesis
Implicated in the pathogenesis
of post-transplantation and conAtriggered hepatic damage
Implicated in acetaminophen
hepatotoxicity
NLRP3
[134, 145149]
[125, 126,
151, 152]
[138]
[153, 154]
[129, 130]
AGER, advanced glycosylation end product-specific receptor; conA, concanavalin A; CRT, calreticulin; DAMP, damage-associated molecular pattern; ER, endoplasmic
reticulum; FPR1, formyl peptide receptor 1; HBV, hepatitis B virus; HMGB1, high mobility group box 1; HSP, heat-shock protein; IL, interleukin; ILRL1, IL receptor-like 1; IR,
ischemia reperfusion; mtDNA, mitochondrial DNA; nDNA nuclear DNA; NLRP3, NOD-like receptor family, pyrin domain containing 3; NMP, nuclear membrane permeabilization; PANX1, pannexin 1; PMP; plasma membrane permeabilization; S1P, sphingosine-1-phosphate; S1PR, S1P receptor; SIGLEC10, sialic acid-binding Ig-like lectin
10; TLR, Toll-like receptor.
protein HMGB1 gets massively released by the hepatocytes of
patients undergoing acute liver failure [144,145] as well as in
rodent models of hepatic IR [146,147], hepatitis B virus (HBV)
infection [148] and concavalin A intoxication [145,149], de facto
playing a major etiological role in these settings (as demonstrated by pharmacological and genetic experiments). Upon binding to TLR9, nuclear DNA released by acetaminophen-exposed
hepatocytes promotes the differentiation of hepatic stellate cells
(HSCs), hence favoring the secretion of collagen and other fibrosis-associated factors [150], as well as the production of proinflammatory cytokines such as IL-1b and IL-18 by tissue-resident and freshly recruited immune cells [151]. The circulating
levels of mitochondrial DNA and N-formyl peptides, both of
which are reminiscent of the endosymbiotic origin of these
organelles, are elevated in patients undergoing acute liver failure
[152]. Moreover, Tlr9/ deficient mice as well as animals receiving a blocking anti-formyl peptide receptor 1 (FPR1) antibody are
protected against acetaminophen-induced liver injury [152]. In
rats, the inhibition of sphingosine kinase 2, one of the enzymes
that generate the pro-inflammatory ceramide derivative S1P
[131], has been shown to suppress inflammation and to attenuate
hepatic damage upon transplantation [153]. Conversely, chemical
agonists of the S1P receptor reportedly protect mice from concanavalin A hepatotoxicity [154]. Along similar lines, several potentially immunogenic HSPs, such as HSPA1A and HSPB1 [135,136],
have been implicated in the hepatic response to IR and other hepatotoxic challenges, yet the major role of these proteins in this
context seems to relate to their capacity to exert cytoprotective
effects by operating as intracellular chaperones [155,156]. Furthermore, the circulating levels of IL-33 are elevated in patients
Journal of Hepatology 2013 vol. 59 j 583–594
589
Review
tory stimuli, HSCs proliferate in response to TLR4-mediated signals and to TGFb produced by Kupffer cells [162]. However, as
chronic inflammation fails to resolve, HSCs progressively acquire
a senescent phenotype, hence manifesting a permanent cell cycle
arrest as well as an increased secretion of specific cytokines (e.g.,
IL-6, IL-8, IL-11) and extracellular matrix-degrading enzymes
[161]. Moreover, the expression of high levels of natural killer
(NK)-cell activating receptor ligands (e.g., MICA, ULBP2, PVR) on
the surface of senescent HSCs for allows their elimination by tissue-resident NK cells, an immunosurveillance mechanism that
contributes to the resolution of fibrosis [161].
Although this pathway associating hepatic fibrosis, senescence,
and immunosurveillance has been primarily described in a model
of acute liver intoxication, the immune system may similarly be
involved in the development of severe or chronic liver pathologies
such as cirrhosis and hepatocellular carcinoma, especially in the
context of immunosuppressed and/or aged patients [163].
Autophagic control
Fig. 3. Damage-associated molecular patterns link inflammation to cell death
in the liver. (A) Upon exposure to most, if not all, hepatotoxic conditions,
hepatocytes as well as liver-resident immune cells (e.g., Kupffer cells, natural
killer [NK] cells; natural killer T [NKT] cells) activate adaptive responses including
autophagy, in an attempt to cope with stress. This generally results in mild
inflammation coupled to the recruitment and local differentiation of circulating
immune cells (mainly monocytes), contributing to the re-establishment of
homeostasis. (B) When such adaptive responses fail, however, stressed hepatocytes undergo apoptosis or necrosis, resulting in the massive release of damageassociated molecular patterns (DAMPs) into the extracellular microenvironment.
By binding to specific pattern-recognition receptors expressed by liver-resident
and freshly recruited immune cells, DAMPs exert potent immunomodulatory
(most often immunostimulatory) functions, hence aggravating the ongoing
inflammatory response. In this setting, immune cells are stimulated to secrete a
wide panel of pro-inflammatory and hepatotoxic factors, leading to a vicious
cycle connecting inflammation and cell death that mediates severe hepatotoxic
effects. DC, dendritic cell.
with acute or chronic liver failure [157], and IL-33 is released by
the hepatocytes of mice exposed to hepatic IR [158] or treated
with concavalin A [159], yet appears to mediate anti-inflammatory, rather than pro-inflammatory, effects.
Taken together, these observations indicate that DAMPs often
constitute major etiological determinants of hepatic diseases as
they control, most often stimulating, a vicious cycle bridging cell
death and inflammation in the liver (Fig. 3).
In hepatocytes, autophagy contributes to the removal of damaged (and hence potentially toxic) mitochondria [33] as well as
to the control of the intracellular lipidome [164]. The selective
autophagic degradation of mitochondria (also known as mitophagy) can be initiated by MOMP and often involves a well characterized signal transduction pathway centered on the
interaction between parkin and PTEN-induced putative kinase
1 (PINK1), two proteins that are mutated in familial Parkinson’s
disease [33]. By preserving the functional pool of mitochondria,
autophagy minimizes ROS generation, hence quenching the activation of intracellular pro-inflammatory factors including the
NLRP3 inflammasome and NF-jB [165]. Along similar lines,
autophagy is required for the normal intracellular metabolism
of lipids, as autophagic defects are associated with an increased
accumulation of triglycerides, in vitro and in vivo [164]. Both
these functions of autophagy are particularly important in the
liver, as various hepatic disorders (i) are accompanied by mitochondrial dysfunction and ROS overproduction [112], and/or
(ii) are associated with the accumulation of lipids in the hepatic
parenchyma [109,115]. In addition, autophagy has recently been
shown to inhibit the release of mitochondrial DNA by cardiomyocytes in vivo, thus limiting the activation of the NLRP3
inflammasome and the pathological consequence of pressure
overload [125]. Furthermore, HMGB1 appears to stimulate
autophagy (while inhibiting cell death) upon binding to
advanced glycosylation end product-specific receptor (AGER,
best known as RAGE) on the surface of pancreatic tumor cells
[166]. It remains to be determined whether similar processes
also occur in the liver.
Endogenous control of inflammation
Besides the removal of apoptotic corpses and necrotic cells by
phagocytes, which limits inflammation as it reduces the availability of DAMPs [160], two additional mechanisms have been shown
to operate an endogenous control over hepatic inflammation,
namely, cellular senescence and autophagy.
Senescence control
The accumulation of senescent HSCs is one of the hallmarks of
some forms of fibrotic liver injury [161]. In response to inflamma590
Conclusions and perspectives
The incidence of hepatic pathologies in developed countries is
constantly increasing owing to multiple lifestyle factors (e.g.,
excessive caloric intake, unbalanced diet, lack of physical exercise, abuse of hepatotoxic drugs) coupled to an augmented life
expectancy. Given the central role of cell death and inflammation
in the etiology of most, if not all, liver disorders, one valid therapeutic strategy may involve the use of hepatoprotective and antiinflammatory interventions, either alone or combined. Clinical
Journal of Hepatology 2013 vol. 59 j 583–594
JOURNAL OF HEPATOLOGY
trials are currently underway to test this hypothesis in cohorts of
patients affected by a wide variety of hepatic conditions (source
www.clinicaltrials.gov).
Recently, DAMPs and the corresponding PRRs have attracted
great attention as candidate targets for the therapy of acute
inflammatory disorders such as the systemic inflammatory
response syndrome (SIRS) [17,126], but their prominent role in
hepatic disorders has just begun to emerge. We surmise that
the precise characterization of the molecular mechanisms and
cellular actors whereby specific DAMPs modulate hepatic inflammatory responses will lead to the development of novel and
effective hepatoprotective measures.
Conflict of interest
The authors declared that they do not have anything to disclose
regarding funding or conflict of interest with respect to this
manuscript.
Acknowledgments
C.B. is senior scientist at the Centre National de la Recherche Scientifique and is a member of the LabEx LERMIT supported by a
grant from the Agence National de la Recherche (ANR) (ANR10-LABX-33). G.K. is supported by the European Commission
(ArtForce); ANR; Ligue contre le Cancer (Equipe labellisée); Fondation pour la Recherche Médicale (FRM); Institut National du
Cancer (INCa); LabEx Immuno-Oncologie; Fondation de France;
Fondation Bettencourt-Schueller; AXA Chair for Longevity Research; Cancéropôle Ile-de-France; Paris Alliance of Cancer Research Institutes (PACRI) and Cancer Research for Personalized
Medicine (CARPEM).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jhep.2013.
03.033.
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