Absent in melanoma (AIM2) but present in ascitic fluid macrophages from patients with cirrhosis
Authors: Thierry Gustot
Journal: Journal of Hepatology (2014)

Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosisJournal of HepatologyVol. 62Issue 1PreviewA key innate immune response that is often associated with sterile inflammation is the rapid activation of cytosolic protein complexes termed inflammasomes [1]. Full activation of the inflammasome requires two different signals. The first signal is provided by the engagement of pattern recognition receptors (PRRs), mainly Toll-like receptors (TLRs), resulting in the transcriptional upregulation and accumulation of inactive pro-IL-1β and pro-IL-18 inside the cell. The second signal can be provided by a plethora of molecules, including microbial motifs known as pathogen-associated molecular patterns (PAMPs), as well as host-derived signals known as damage-associated molecular patterns (DAMPs) that are released as a result of tissue damage or cellular stress. Full-Text PDF Decompensation of cirrhosis, in particular acute-on chronic liver failure (ACLF), is associated with a systemic inflammatory response that is characterized by high leukocyte counts and high plasma C-reactive protein levels, and has been correlated with higher mortality [[1]Moreau R. Jalan R. Gines P. Pavesi M. Angeli P. Cordoba J. et al.Acute-on-Chronic Liver Failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437Abstract Full Text Full Text PDF PubMed Scopus (1658) Google Scholar]. The triggers of this inflammation are currently unknown. Overt bacterial infection might explain a part of it, but the association between the severity of decompensation and systemic inflammation is also observed in non-infected patients. This systemic inflammation could be driven by enhanced translocation of viable intestinal microorganisms to mesenteric lymph nodes, bacteria-derived products (pathogen associated molecular patterns, PAMPs), or by mediators, released by “sterile” injured tissue (damage-associated molecular patterns, DAMPs). Increased bacterial translocation of viable bacteria and bacterial products is observed and permitted by increased intestinal permeability, which is partially due to alterations in tight junction (TJ) proteins in the advanced stages of cirrhosis [[2]Assimakopoulos S.F. Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: the pivotal role of enterocyte tight junctions and future perspectives.J Hepatol. 2013; 59: 1144-1146Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Some PAMPs, such as lipopolysaccharide (LPS) and bacterial DNA (bactDNA), have been detected in the blood of patients with decompensated cirrhosis [[3]Such J. Frances R. Munoz C. Zapater P. Casellas J.A. Cifuentes A. et al.Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative nonneutrocytic ascites.Hepatology. 2002; 36: 135-141Crossref PubMed Scopus (237) Google Scholar]. The innate immune system is the first line of defence against microbial infection and is activated by the engagement of germline-encoded pattern recognition receptors (PRRs) in response to microbes. PRRs include the membrane-bound Toll-like receptors (TLRs) and C-type lectins, which scan the extracellular milieu and endosomal compartments for PAMPs. On one hand, activation of TLRs on the cell surface results in the release of many cytokines, including TNF-α, IL-6, and IL-12 [[4]Akira S. Takeda K. Toll-like receptor signaling.Nat Rev Immunol. 2004; 4: 499-511Crossref PubMed Scopus (6564) Google Scholar]. On the other hand, engagement of TLRs induces the production but not secretion of pro-IL-1β and pro-IL-18. Intracellular PRRs cooperate in a multi-protein complex, called the inflammasome to provide cytosolic surveillance and to activate caspase-1, which proteolytically cleaves the cytosol-sequestering leader sequence of pro-IL-1β and pro-IL-18 to generate and release mature cytokines [[5]Schroder K. Tschopp J. The inflammasomes.Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (3959) Google Scholar]. Membrane bound and intracellular PRRs cooperate to fully activate IL-1β and IL-18 release. Absent in melanoma 2 (AIM2) has been recently identified as a cytosolic double-stranded DNA (dsDNA) sensor, contributing to the inflammasome complex by combining with ASC and caspase-1 [[6]Hornung V. Ablasser A. Charrel-Dennis M. Bauernfeind F. Horvath G. Caffrey D.R. et al.AIM2 recognizes cytosolic dsDNA and forms a caspase 1 activating inflammasome with ASC.Nature. 2009; 458: 514-518Crossref PubMed Scopus (1727) Google Scholar]. The ligands of AIM2 are cytosolic dsDNAs, coming from viruses, bacteria, and the host. Cirrhosis is classically associated with a systemic inflammation, characterized by enhanced expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-18) in the serum and in peripheral blood mononuclear cells, which overproduce ex vivo pro-inflammatory cytokines in response to LPS, the TLR4 ligand [7Khoruts A. Stanke L. McClain C.J. Logan G. Allen J.I. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients.Hepatology. 1991; 13: 267-276Crossref PubMed Scopus (501) Google Scholar, 8Ludwiczed O. Kaser A. Novick D. Dinarello C.A. Rubinstein M. Vogel W. et al.Plasma levels of interleukin-18 and interleukin-18 binding protein are elevated in patients with chronic liver disease.J Clin Immunol. 2002; 22: 331-337Crossref PubMed Scopus (63) Google Scholar, 9Coant N. Simon-Rudler M. Gustot T. Fasseu M. Gandoura S. Ragot K. et al.Glycogen synthase kinase 3 involvement in the excessive proinflammatory response to LPS in patients with decompensated cirrhosis.J Hepatol. 2011; 55: 784-793Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Several mechanisms at least partially explain this overexpression. LPS-stimulated monocytes from patients with cirrhosis display a lack of interleukin-1 receptor-associated kinase (IRAK)-M induction, decreased Akt activity, defects in glycogen synthase kinase (GSK)3β phosphorylation, and reduced expression of IL-10, contributing to the loss of counter-regulatory mechanisms of the TLR4 pathway and the hyper-production of TNF-α [9Coant N. Simon-Rudler M. Gustot T. Fasseu M. Gandoura S. 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The implications of the inflammasome and its dependent cytokine (IL-1β and IL-18) activation in various forms of liver disease, including liver damage, steatosis, inflammation, and fibrosis are extensively discussed elsewhere [[12]Szabo G. Csak T. Inflammasomes in liver diseases.J Hepatol. 2012; 57: 642-654Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar]. However, the inflammasome-dependent IL-1β and IL-18 pathways in cirrhosis were unexplored until publication of the study by Lozano-Ruiz and colleagues in the current issue of the Journal of Hepatology [[13]Lozano-Ruiz B. Bachiller V. Garcia-Martinez I. Zapater P. Gomez-Hurtado I. Moratalla A. et al.Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis.J Hepatol. 2015; 62: 64-71Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. The authors observed a primed state of ascitic fluid (AF) macrophages in patients with cirrhosis that was characterized by increased expression of pro-IL 1β and pro-IL 18 mRNA, activation of caspase-1, and enhanced expression of AIM2. This pre-activated state allowed AF macrophages to produce high amounts of mature IL-1β and IL-18 in response to the AIM2 ligand, dsDNA, without the requirement of a priming stimulation by extracellular PAMPs. Moreover, the presence of bactDNA in ascites was associated with an enhanced AIM2-related pre-activated state, suggesting that translocation of bactDNA could be responsible for this priming. This study highlights the compartmentalization of the activation of innate immune cells in cirrhosis. Compared to AF CD14+ cells, circulating CD14+ monocytes did not display an AIM2-related pre-activated state. Detailed study of the activation pattern of AF leukocytes should offer the interesting future opportunity to better understand the inflammation process in cirrhosis and its compartmentalization. The AIM2-related pre-activated state of AF macrophages was also correlated with the severity of cirrhosis. Indeed, IL-1β and IL-18 production by AF macrophages in response to dsDNA was enhanced in patients with Child-Pugh C cirrhosis, compared to those with Child-Pugh B. The authors also observed that higher production of IL-18 in AF is a Child-Pugh score-independent predictor of the occurrence of spontaneous bacterial peritonitis. Caspase-1 and IL-18 levels are higher in patients with ACLF compared to patients with stable chronic liver disease [[14]Roth G.A. Faybik P. Hetz H. Hacker S. Ankersmit H.J. Bacher A. et al.Pro-inflammatory interleukin-18 and Caspase-1 serum levels in liver failure are unaffected by MARS treatment.Dig Liver Dis. 2009; 41: 417-423Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Taken together, these data suggest that the inflammasome is primed in advanced cirrhosis and its activation is linked to the severity of liver disease. At this time, it is difficult to define whether inflammasome activation contributes to the progression of cirrhosis and the occurrence of decompensation or is only a surrogate marker, associated with the severity of liver disease. The authors suggest a ‘two-hit’ process for cirrhotic decompensation, in which the initial activation of AF leukocytes by extracellular PAMPs, e.g. bactDNA, coming from translocation, is followed by activation of a second inflammasome ligand such as DAMPs, e.g. host dsDNA. Sterile activation of innate immunity in cirrhosis is attractive but clearly hypothetical at this time. Further translational studies, with deep assessment of molecular modifications and detection of triggers, such as PAMPs and DAMPs, of the innate immune system in patients with cirrhosis, are clearly needed to suggest new areas of research and to potentially provide substantial improvement in outcomes for these patients. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.