The Pathogenesis of ACLF: The Inflammatory Response and Immune Function

Abstract

Although systemic inflammation is a hallmark of acute-on-chronic liver failure (ACLF), its role in the development of this syndrome is poorly understood. Here the author first summarizes the general principles of the inflammatory response. Inflammation can be triggered by exogenous or endogenous inducers. Important exogenous inducers include bacterial products such as pathogen-associated molecular patterns (PAMPs) and virulence factors. Pathogen-associated molecular patterns elicit inflammation through structural feature recognition (using innate pattern-recognition receptors [PRRs]), whereas virulence factors generally trigger inflammation via functional feature recognition. Endogenous inducers are called danger-associated molecular patterns (DAMPs) and include molecules released by necrotic cells and products of extracellular matrix breakdown. Danger-associated molecular patterns use different PRRs. The purpose of the inflammatory response may differ according to the type of stimulus: The aim of infection-induced inflammation is to decrease pathogen burden, whereas the DAMP-induced inflammation aims to promote tissue repair. An excessive inflammatory response can induce collateral tissue damage (a process called immunopathology). However immunopathology may not be the only mechanism of tissue damage; for example, organ failure can develop because of failed disease tolerance. In this review, the author also discusses how general principles of the inflammatory response can help us to understand the development of ACLF in different contexts: bacterial infection, severe alcoholic hepatitis, and cases in which there is no identifiable trigger.

Keywords

inflammation - pattern recognition receptors - immunopathology - tolerance - cirrhosis

• References

• 1 Moreau R, Jalan R, Gines P , et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (7) 1426-1437 , 1437.e1–1437.e9
• 2 Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454 (7203) 428-435
• 3 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140 (6) 805-820
• 4 Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol 2015; 16 (4) 343-353
• 5 Zhao Y, Yang J, Shi J , et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 2011; 477 (7366) 596-600
• 6 Kayagaki N, Wong MT, Stowe IB , et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 2013; 341 (6151) 1246-1249
• 7 Shi J, Zhao Y, Wang Y , et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014; 514 (7521) 187-192
• 8 Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27: 229-265
• 9 Xu H, Yang J, Gao W , et al. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 2014; 513 (7517) 237-241
• 10 Moura-Alves P, Faé K, Houthuys E , et al. AhR sensing of bacterial pigments regulates antibacterial defence. Nature 2014; 512 (7515) 387-392
• 11 Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008; 8 (4) 279-289
• 12 Rickard JA, O'Donnell JA, Evans JM , et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 2014; 157 (5) 1175-1188
• 13 Zhang Q, Raoof M, Chen Y , et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464 (7285) 104-107
• 14 Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science 2012; 335 (6071) 936-941
• 15 Jamieson AM, Pasman L, Yu S , et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 2013; 340 (6137) 1230-1234
• 16 Zaiss DM, Gause WC, Osborne LC, Artis D. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 2015; 42 (2) 216-226
• 17 Figueiredo N, Chora A, Raquel H , et al. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 2013; 39 (5) 874-884
• 18 Jalan R, Fernandez J, Wiest R , et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014; 60 (6) 1310-1324
• 19 Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014; 60 (1) 197-209
• 20 Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63 (5) 1272-1284
• 21 Navasa M, Follo A, Filella X , et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology 1998; 27 (5) 1227-1232
• 22 Hugot JP, Chamaillard M, Zouali H , et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411 (6837) 599-603
• 23 Appenrodt B, Grünhage F, Gentemann MG, Thyssen L, Sauerbruch T, Lammert F. Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology 2010; 51 (4) 1327-1333
• 24 Nish S, Medzhitov R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity 2011; 34 (5) 629-636
• 25 Orozco LD, Bennett BJ, Farber CR , et al. Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell 2012; 151 (3) 658-670
• 26 Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009; 360 (26) 2758-2769
• 27 Dominguez M, Miquel R, Colmenero J , et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 2009; 136 (5) 1639-1650
• 28 Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006; 354 (6) 610-621
• 29 Altamirano J, Miquel R, Katoonizadeh A , et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014; 146 (5) 1231-9.e1 , 6
• 30 Zhang K, Shen X, Wu J , et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 2006; 124 (3) 587-599
• 31 Tazi KA, Bièche I, Paradis V , et al. In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats. J Hepatol 2007; 46 (6) 1075-1088
• 32 Chovatiya R, Medzhitov R. Stress, inflammation, and defense of homeostasis. Mol Cell 2014; 54 (2) 281-288
• 33 Singh V, Sharma AK, Narasimhan RL, Bhalla A, Sharma N, Sharma R. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol 2014; 109 (9) 1417-1423
• 34 Dubuquoy L, Louvet A, Lassailly G , et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut 2015; 64 (12) 1949-1960
• 35 Michelena J, Altamirano J, Abraldes JG , et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology 2015; 62 (3) 762-772
• 36 Qin N, Yang F, Li A , et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014; 513 (7516) 59-64
• 37 Bajaj JS, Heuman DM, Hylemon PB , et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (5) 940-947
• 38 Bajaj JS, Ridlon JM, Hylemon PB , et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 2012; 302 (1) G168-G175
• 39 Chen Y, Yang F, Lu H , et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (2) 562-572
• 40 Chen Y, Guo J, Qian G , et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol 2015; 30 (9) 1429-1437
• 41 Bauer TM, Schwacha H, Steinbrückner B , et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 2002; 97 (9) 2364-2370
• 42 Zapater P, Francés R, González-Navajas JM , et al. Serum and ascitic fluid bacterial DNA: a new independent prognostic factor in noninfected patients with cirrhosis. Hepatology 2008; 48 (6) 1924-1931
• 43 Bernsmeier C, Pop OT, Singanayagam A , et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 2015; 148 (3) 603-615.e14
• 44 Zagórska A, Través PG, Lew ED, Dransfield I, Lemke G. Diversification of TAM receptor tyrosine kinase function. Nat Immunol 2014; 15 (10) 920-928
• 45 O'Brien AJ, Fullerton JN, Massey KA , et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med 2014; 20 (5) 518-523
• 46 Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13 (12) 862-874
• 47 Wasmuth HE, Kunz D, Yagmur E , et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42 (2) 195-201