title: Decoding cell death signals in liver inflammation.
abstract: 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 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.
authors.affiliation: INSERM, UMRS 769, LabEx LERMIT, F-92290 Châtenay Malabry, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D016923:Cell Death / Q000502:physiology*; D016922:Cellular Senescence; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006505:Hepatitis / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008055:Lipids / Q000502:physiology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008954:Models, Biological; D018384:Oxidative Stress; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha
keywords: 5-lipoxygenase activating protein; AGER; ALOX5; ANT; ASK1; ATF6; Apoptosis; C/EPB homologous protein; CFLAR; CHOP; COX2; CRT; DAMP; DAPK1; DCC; DIABLO; ECP; EDN; EGFR; EIF2AK3; EP; ER; ERN1; FFA; FLAP; FPR1; GADD34; GM-CSF; GRP78; GSK-3β; HBV; HCV; HFD; HMGB1; HSC; HSP; IFNγ; IL; IL-1 receptor antagonist; IL-1RA; IR; IRE1α; JNK; LPS; Lipotoxicity; MAMP; MAPK; MBP; MLKL; MOMP; NADPH oxidase; NAFLD; NASH; NK; NO; NO synthase; NOS; NOX; NSAID; Necrosis; Non-alcoholic necrosis steatohepatitis; PERK; PGAM5; PGE; PGE receptor 1, subtype EP1; PINK1; PKR-related ER kinase; PP1; PRR; PTEN-induced putative kinase 1; PTGER1; PTPC; Pattern recognition receptors; RIPK1; RNS; ROS; S1P; SIGLEC10; SIRS; STAT3; TGFβ; TLR; TNF receptor 1; TNF-related apoptosis inducing ligand; TNFR1; TNFα; TRAIL; Toll-like receptor; Tumor necrosis factor receptor; UPR; VDAC; aSMase; acidic sphingomyelinase; activating transcription factor 6; adenine nucleotide translocase; advanced glycosylation end product-specific receptor; apoptosis signal-regulating kinase 1; arachidonate 5-lipoxygenase; c-Jun N-terminal kinase; calreticulin; caspase-8 and FADD-like apoptosis regulator; cyclooxygenase 2; damage-associated molecular pattern; death-associated protein kinase 1; deleted in colorectal carcinoma; direct IAP-binding protein with low pI; eIF2α; eIF2α kinase 3; eNOS; endoplasmic reticulum; endoplasmic reticulum to nucleus signaling 1; endothelial NOS; eosinophil cationic protein; eosinophil peroxidase; eosinophil-derived neurotoxin; epidermal growth factor receptor; eukaryotic translation initiation factor 2α; formyl peptide receptor 1; free fatty acid; glucose-regulated protein, 78kDa; glycogen synthase kinase 3β; granulocyte macrophage colony stimulating factor; growth arrest- and DNA damage-inducible gene 34; heat-shock protein; hepatic stellate cell; hepatitis B virus; hepatitis C virus; high mobility group box 1; high-fat diet; iNOS; inducible NOS; inositol-requiring enzyme 1α; interferon γ; interleukin; ischemia/reperfusion; lipopolysaccharide; major basic protein; microbe-associated molecular pattern; mitochondrial outer membrane permeabilization; mitochondrial transmembrane potential; mitogen-activated protein kinase; mixed lineage kinase domain-like; natural killer; nitric oxide; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; non-steroidal anti-inflammatory drug; pattern recognition receptor; permeability transition pore complex; phosphoglycerate mutase family member 5; prostaglandin E; protein phosphatase 1; reactive nitrogen species; reactive oxygen species; receptor-interacting protein kinase 1; sialic acid-binding Ig-like lectin 10; signal transducer and activator of transcription 3; sphingosine-1-phosphate; systemic inflammatory response syndrome; transforming growth factor β; tumor necrosis factor α; unfolded protein response; voltage-dependent anion channel; Δψ(m)