Inflammasomes in liver diseases

Inflammation is a common element in the pathogenesis of most chronic liver diseases that lead to fibrosis and cirrhosis. Inflammation is characterized by activation of innate immune cells and production of pro-inflammatory cytokines IL-1α, IL-1β, and TNFα. Inflammasomes are intracellular multiprotein complexes expressed in both parenchymal and non-parenchymal cells of the liver that in response to cellular danger signals activate caspase-1, and release IL-1β and IL-18. The importance of inflammasome activation in various forms of liver diseases in relation to liver damage, steatosis, inflammation and fibrosis is discussed in this review. Inflammation is a common element in the pathogenesis of most chronic liver diseases that lead to fibrosis and cirrhosis. Inflammation is characterized by activation of innate immune cells and production of pro-inflammatory cytokines IL-1α, IL-1β, and TNFα. Inflammasomes are intracellular multiprotein complexes expressed in both parenchymal and non-parenchymal cells of the liver that in response to cellular danger signals activate caspase-1, and release IL-1β and IL-18. The importance of inflammasome activation in various forms of liver diseases in relation to liver damage, steatosis, inflammation and fibrosis is discussed in this review. The term “inflammasome”, introduced by Tschopp and colleagues [[1]Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.Mol Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar] refers to large multiprotein complexes that sense intracellular danger signals via NOD-like receptors (NLR) [[2]Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar]. NOD-like receptors, members of the pattern recognition receptor family, contain a C-terminal leucin-rich-repeat (LRR) domain that plays a role in the recognition of ligands, a central NACHT domain that is responsible for the oligomerization and dNTPase activity, and an N-terminal CARD, pyrin (PYD), BIR (baculoviral inhibitory repeat), or acidic transactivation domain. Based on the NACHT domain, three subfamilies of proteins are defined: (a) NODs, (NOD1–5, CIITA), (b) NLRPs or NALPs (NLRP/NALP 1–14), and (c) IPAF (IPAF, NAIP) subfamily [[2]Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar] (summarized in Fig. 1). Other classifications, based on the N-terminal effector domain, are also known [[3]Ye Z. Ting J.P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.Curr Opin Immunol. 2008; 20: 3-9Crossref PubMed Scopus (113) Google Scholar]. Several, but not all, NLRs play a role in the formation of inflammasomes. With the exception of AIM2, which is a member of the HIN-200 family, the nomenclature of inflammasomes is based on the NOD-like receptor (NLR).Fig. 1Structure of inflammasome and non-inflammasome NLRs and non-NLR inflammasomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The sensor, NLR, forms a complex with the effector molecule, pro-caspase-1, with or without the contribution of an adapter molecule, such as the apoptosis-associated speck like CARD-domain containing protein (ASC) [1Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.Mol Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar, 2Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar, 3Ye Z. Ting J.P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.Curr Opin Immunol. 2008; 20: 3-9Crossref PubMed Scopus (113) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar]. Inflammasome activation leads to auto-activation of the 45 kDa inactive pro-caspase-1 precursor into p20 and p10 subunits that form the active caspase-1 [1Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.Mol Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar, 2Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar, 3Ye Z. Ting J.P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.Curr Opin Immunol. 2008; 20: 3-9Crossref PubMed Scopus (113) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar], resulting in the cleavage of pro-IL-1β and pro-IL-18 into mature forms, and inactivation of IL-33 [1Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.Mol Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar, 2Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar, 3Ye Z. Ting J.P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.Curr Opin Immunol. 2008; 20: 3-9Crossref PubMed Scopus (113) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar, 5Cayrol C. Girard J.P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1.Proc Natl Acad Sci USA. 2009; 106: 9021-9026Crossref PubMed Scopus (296) Google Scholar]. IL-1β is a pro-inflammatory cytokine, a central regulator of inflammation that binds to the IL-1 receptor (IL-1R) to exert its broad biological effects. IL-1R also recognizes IL-1α and binds IL-1R antagonist (IL-1Ra), the latter inhibiting IL-1R activation [[6]Dinarello C.A. Immunological and inflammatory functions of the interleukin-1 family.Annu Rev Immunol. 2009; 27: 519-550Crossref PubMed Scopus (1190) Google Scholar]. IL-18 activates natural killer (NK) cells to produce IFNγ [[6]Dinarello C.A. Immunological and inflammatory functions of the interleukin-1 family.Annu Rev Immunol. 2009; 27: 519-550Crossref PubMed Scopus (1190) Google Scholar], while IL-33 is a chromatin-associated cytokine of the IL-1 family that drives Th2 responses [4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar, 6Dinarello C.A. Immunological and inflammatory functions of the interleukin-1 family.Annu Rev Immunol. 2009; 27: 519-550Crossref PubMed Scopus (1190) Google Scholar]. The full-length active IL-33 is cleaved and inactivated by caspase-1 [[5]Cayrol C. Girard J.P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1.Proc Natl Acad Sci USA. 2009; 106: 9021-9026Crossref PubMed Scopus (296) Google Scholar]. Inflammasome activation is thought to be a two-step process in which signal 1 (mostly from TLR activation) upregulates inflammasome expression and signal 2 triggers functional inflammasome activation by an inflammasome ligand [2Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar]. A recent publication suggests that the priming step is required only for activation of NLRP3 and not other inflammasomes such as NLRC4 or AIM2 [[7]Bauernfeind F. Bartok E. Rieger A. Franchi L. Nunez G. Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome.J Immunol. 2011; 187: 613-617Crossref PubMed Scopus (187) Google Scholar]. Inflammasome ligands include both pathogen-associated (PAMPs) and endogenous danger molecules (DAMPs) (summerized in Table 1) [1Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.Mol Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar, 2Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar, 3Ye Z. Ting J.P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.Curr Opin Immunol. 2008; 20: 3-9Crossref PubMed Scopus (113) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar]. To date, four main prototypes of inflammasomes have been characterized: NLRP1 (NALP1); NLRP3 (NALP3, cryporin); NLRC4 (IPAF) and AIM2 [2Martinon F. Mayor A. Tschopp J. The inflammasomes: guardians of the body.Annu Rev Immunol. 2009; 27: 229-265Crossref PubMed Scopus (994) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar]. They have different ligand recognition sites and utilization of adapter molecules but all culminate in caspase-1 activation.Table 1Known activators of inflammasome NLRs. Open table in a new tab NLRP1 (NACHT, LRR, and PYD domains-containing protein 1), the first inflammasome described, can directly interact with caspase-1 through its C-terminal CARD domain, and in humans, the presence of ASC enhances the activity of the complex [[34]Schroder K. Tschopp J. The inflammasomes.Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (1384) Google Scholar]. Murine NLRP1 is unable to bind to ASC because it lacks a functional PYD domain [[34]Schroder K. Tschopp J. The inflammasomes.Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (1384) Google Scholar]. Multiple alternatively spliced transcript variants of human NLRP1 exist [[35]Pontillo A. Catamo E. Arosio B. Mari D. Crovella S. NALP1/NLRP1 genetic variants are associated with Alzheimer disease.Alzheimer Dis Assoc Discord. 2011; (Dec. 6 [Epub ahead of print])Google Scholar]. NLRP1 is activated by the muramyl dipeptide (MDP) and the Bacillus anthracis lethal toxin [8Boyden E.D. Dietrich W.F. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.Nat Genet. 2006; 38: 240-244Crossref PubMed Scopus (419) Google Scholar, 9Wickliffe K.E. Leppla S.H. Moayeri M. 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An interaction was reported between NLRP1 and another NLR protein, NOD2, and Hsu et al. found that NLRP1 and NOD2 were both required for MDP or B. anthracis toxin-induced IL-1β secretion [[11]Hsu L.C. et al.A NOD2-NALP1 complex mediates caspase-1-dependent IL-1β secretion in response to Bacillus anthracis infection and muramyl dipeptide.Proc Natl Acad Sci USA. 2008; 105: 7803-7808Crossref PubMed Scopus (204) Google Scholar]. Potassium efflux plays a role in NLRP1 inflammasome activation [[9]Wickliffe K.E. Leppla S.H. Moayeri M. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome.Cell Microbiol. 2008; 10: 332-343Crossref PubMed Scopus (26) Google Scholar] and NLRP1 can localize into the nucleus, and this feature is unique in comparison to the cytoplasmic distribution of other inflammasomes [[36]Kummer J.A. Broekhuizen R. Everett H. Agostini L. Kuijk L. Martinon F. et al.Inflammasome components NALP1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response.J Histochem Cytochem. 2007; 55: 443-452Crossref PubMed Scopus (207) Google Scholar]. NLRP3 (NACHT, LRR, and PYD domains-containing protein 3, cryoporin) was first described by Hoffman et al. who discovered four single mutations in the NLRP3 gene, in families with familial cold autoinflammatory syndrome and Muckle–Wells syndrome, which lead to increased IL-1β production [[37]Hoffman H.M. Mueller J.L. Broide D.H. Wanderer A.A. Kolodner R.D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome.Nat Genet. 2001; 29: 301-305Crossref PubMed Scopus (777) Google Scholar]. Later, Agostini et al. reported that NLRP3 forms an IL-1β-processing inflammasome complex [[38]Agostini L. Martinon F. Burns K. McDermott M.F. Hawkins P.N. Tschopp J. NALP3 forms an IL-1β processing inflammasome with increased activity in Muckle–Wells auto-inflammatory disorder.Immunity. 2004; 20: 319-325Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar]. To date, NLRP3 is the most fully characterized member of the inflammasome family. It consists of the NOD-like receptor NLRP3, the adaptor molecule ASC, and the effector molecule pro-caspase-1. Since NLRP3 does not contain a CARD domain, the presence of the adaptor molecule is necessary for the complex formation [[34]Schroder K. Tschopp J. The inflammasomes.Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (1384) Google Scholar]. The expression of NLRP3 is tightly regulated at the transcriptional level via NFκB [[39]Bauernfeind F.G. Horvath G. Stutz A. Alnemri E.S. MacDonald K. Speert D. et al.Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.J Immunol. 2009; 183: 787-791Crossref PubMed Scopus (511) Google Scholar]. NLRP3 activation requires two signals. Cell priming with an NFκB activator, such as the TLR4-ligand LPS, is the first step of NLRP3 inflammasome activation [[39]Bauernfeind F.G. Horvath G. Stutz A. Alnemri E.S. MacDonald K. Speert D. et al.Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.J Immunol. 2009; 183: 787-791Crossref PubMed Scopus (511) Google Scholar] leading to up regulation of NLRP3 expression [[39]Bauernfeind F.G. Horvath G. Stutz A. Alnemri E.S. MacDonald K. 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Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.Science. 2008; 320: 674-677Crossref PubMed Scopus (1006) Google Scholar, 16Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. et al.The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta.Nat Immunol. 2008; 9: 857-865Crossref PubMed Scopus (703) Google Scholar, 17Yamasaki K. Muto J. Taylor K.R. Cogen A.L. Audish D. Bertin J. et al.NLRP3/cryoporin is necessary for interleukin-1beta (IL-1beta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.J Biol Chem. 2009; 284: 12762-12771Crossref PubMed Scopus (128) Google Scholar, 18Dostert C. Guarda G. Romero J.F. Menu P. Gross O. Tardivel A. et al.Malarial hemozoin is a Nalp3 inflammasome activating danger signal.PloS One. 2009; 4: e6510Crossref PubMed Scopus (175) Google Scholar, 19Sharp F.A. Ruane D. Claass B. Creaqh E. Harris J. Malyala P. et al.Uptake of particulate vaccine adjuvants by dendritic cells activate the NALP3 inflammasome.Proc Natl Acad Sci USA. 2009; 106: 870-875Crossref PubMed Scopus (225) Google Scholar, 20Duewell P. Kono H. Rayner K.J. Sirois C.M. Vladimer G. Bauernfeind F.G. et al.NLRP3 inflammasome are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361Crossref PubMed Scopus (836) Google Scholar]. It has been shown that disruption of lysosomes by chemical damage [[41]Gong Y.N. Wang X. Wang J. Yang Z. Li S. Yang J. et al.Chemical probing reveals insights into the signaling mechanism of inflammasome activation.Cell Res. 2010; 20: 1289-1305Crossref PubMed Scopus (28) Google Scholar] or lysosomal damage after phagocytosis of these large particles induces NLRP3 inflammasome activation [14Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. et al.Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization.Nat Immunol. 2008; 9: 847-856Crossref PubMed Scopus (1024) Google Scholar, 16Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. et al.The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta.Nat Immunol. 2008; 9: 857-865Crossref PubMed Scopus (703) Google Scholar, 20Duewell P. Kono H. Rayner K.J. Sirois C.M. Vladimer G. Bauernfeind F.G. et al.NLRP3 inflammasome are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361Crossref PubMed Scopus (836) Google Scholar]. Consistent with the role of lysosomal damage in inflammasome activation, the role of a lysosomal protease, cathepsin B, has been implicated in certain forms of NLRP3 activation [4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (148) Google Scholar, 18Dostert C. Guarda G. Romero J.F. Menu P. Gross O. Tardivel A. et al.Malarial hemozoin is a Nalp3 inflammasome activating danger signal.PloS One. 2009; 4: e6510Crossref PubMed Scopus (175) Google Scholar, 42Tschopp J. Schroder K. NLRP3 inflammasome activation: the convergence of multiple signaling pathways on ROS production?.Nat Rev Immunol. 2010; 10: 210-215Crossref PubMed Scopus (437) Google Scholar]. Third, some studies suggest that reactive oxygen species (ROS) contribute to inflammasome activation. This is based on the observation that inhibitors or scavengers that block mitochondrial ROS or NADPH oxidase suppress inflammasome activation [4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. 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