Inflammasomes in pancreatic physiology and disease

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 308, Issue 8, 2015, Pages G643-G651

  Hoque, Rafaz ^a   Mehal, Wajahat Z ^a,b  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VA CONNECTICUT HEALTHCARE SYSTEM   (United States)

Author keywords

And PYD domains containing protein 3; G protein coupled receptor 109a; G protein coupled receptor 81; LRR; Mitochondrial oxidation; NACHT

Indexed keywords

CRYOPYRIN; INFLAMMASOME; INTERLEUKIN 18; INTERLEUKIN 1BETA; AUTACOID;

ACINAR CELL; ACUTE PANCREATITIS; BONE MARROW CELL; CELL DEATH; CELL SPECIFICITY; HUMAN; INTESTINE FLORA; INTRACELLULAR SIGNALING; LIPID DIET; METABOLIC REGULATION; MITOCHONDRIAL RESPIRATION; NONHUMAN; PANCREAS FUNCTION; PANCREATIC STELLATE CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; ANIMAL; IMMUNOLOGY; INNATE IMMUNITY; METABOLISM; PANCREAS; PANCREAS DISEASE; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; IMMUNITY, INNATE; INFLAMMASOMES; INFLAMMATION MEDIATORS; PANCREAS; PANCREATIC DISEASES; SIGNAL TRANSDUCTION;

EID: 84929625408     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00388.2014     Document Type: Review

References (101)

1. Aiba-Masago S, Masago R, Vela-Roch N, Talal N, Dang H. Fasmediated apoptosis in a rat acinar cell line is dependent on caspase-1 activity. Cell Signal 13: 617–624, 2001.
2. Ammori BJ. Role of the gut in the course of severe acute pancreatitis. Pancreas 26: 122–129, 2003.
3. Bae J, Ricciardi CJ, Esposito D, Komarnytsky S, Hu P, Curry BJ, Brown PL, Gao Z, Biggerstaff JP, Chen J, Zhao L. Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. Am J Physiol Cell Physiol 306: C918–C930, 2014.
4. Bedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A, Ibrahim J, Cieza-Rubio NE, Henning JR, Barilla R, Rehman A, Pachter HL, Medina-Zea MV, Cohen SM, Frey AB, Acehan D, Miller G. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology 141: 1915–1926, 2011.
5. Bhopale KK, Wu H, Boor PJ, Popov VL, Ansari GA, Kaphalia BS. Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice. Alcohol 39: 179–188, 2006.
6. Brydges SD, Broderick L, McGeough MD, Pena CA, Mueller JL, Hoffman HM. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest 123: 4695–4705, 2013.
7. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, Gibson GR, Delzenne NM. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 50: 2374–2383, 2007.
8. Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med 205: 2609–2621, 2008.
9. Cayrol C, Girard JP. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci USA 106: 9021–9026, 2009.
10. Chalkiadaki A, Guarente L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab 16: 180–188, 2012.
11. Chen Y, Choi SS, Michelotti GA, Chan IS, Swiderska-Syn M, Karaca GF, Xie G, Moylan CA, Garibaldi F, Premont R, Suliman HB, Piantadosi CA, Diehl AM. Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology 143: 1319–1329, 2012.
12. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16: 228–231, 2010.
13. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513: 559–563, 2014.
14. Criddle DN, Raraty MG, Neoptolemos JP, Tepikin AV, Petersen OH, Sutton R. Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proc Natl Acad Sci USA 101: 10738–10743, 2004.
15. Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 54: 133– 144, 2011.
16. Dawra R, Sah RP, Dudeja V, Rishi L, Talukdar R, Garg P, Saluja AK. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology 141: 2210–2217, 2011.
17. Denham W, Yang J, Fink G, Denham D, Carter G, Ward K, Norman J. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology 113: 1741–1746, 1997.
18. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145: 745–757, 2011.
19. Farooq A, Hoque R, Ouyang X, Farooq A, Ghani A, Ahsan K, Guerra M, Mehal WZ. Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a _-arrestin- 2 pathway. Am J Physiol Gastrointest Liver Physiol 307: G732–G740, 2014.
20. Felker D, Lynn A, Wang S, Johnson DE. Evidence for a potential protective effect of carnitine-pantothenic acid co-treatment on valproic acid-induced hepatotoxicity. Exp Rev Clin Pharmacol 7: 211–218, 2014.
21. Feng B, Wu S, Lv S, Liu F, Chen H, Yan X, Li Y, Dong F, Wei L. Metabolic profiling analysis of a D-galactosamine/lipopolysaccharideinduced mouse model of fulminant hepatic failure. J Proteome Res 6: 2161–2167, 2007.
22. Galvan-Pena S, O’Neill LA. Metabolic reprograming in macrophage polarization (Abstract). Frontiers Immunol 5: 420, 2014.
23. Gerstner T, Busing D, Bell N, Longin E, Kasper JM, Klostermann W, Hebing B, Hanefeld F, Eckel U, Hoffmann R, Bettendorf U, Weidner B, Wiemer-Kruel A, Brockmann K, Neumann FW, Sandrieser T, Wolff M, Konig S. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 42: 39–48, 2007.
24. Gu H, Werner J, Bergmann F, Whitcomb DC, Buchler MW, Fortunato F. Necro-inflammatory response of pancreatic acinar cells in the pathogenesis of acute alcoholic pancreatitis (Abstract). Cell Death Dis 4: e816, 2013.
25. Gukovsky I, Gukovskaya A. Nuclear factor-kappaB in pancreatitis: Jack-of-all-trades, but which one is more important? Gastroenterology 144: 26–29, 2013.
26. Haanes KA, Schwab A, Novak I. The P2X7 receptor supports both life and death in fibrogenic pancreatic stellate cells. PloS one 7: e51164, 2012.
27. Hasel C, Durr S, Rau B, Strater J, Schmid RM, Walczak H, Bachem MG, Moller P. In chronic pancreatitis, widespread emergence of TRAIL receptors in epithelia coincides with neoexpression of TRAIL by pancreatic stellate cells of early fibrotic areas. Lab Invest 83: 825–836, 2003.
28. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137: 1100–1111, 2009.
29. Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC, Salter RD. Mitochondrial reactive oxygen species induces NLRP3-dependent lyso- somal damage and inflammasome activation. J Immunol 191: 5230–5238, 2013.
30. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1: 489–495, 2000.
31. Hoque R, Farooq A, Ghani A, Gorelick F, Mehal WZ. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasomemediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 146: 1763–1774, 2014.
32. Hoque R, Malik AF, Gorelick F, Mehal WZ. Sterile inflammatory response in acute pancreatitis. Pancreas 41: 353–357, 2012.
33. Hoque R, Sohail M, Malik A, Sarwar S, Luo Y, Shah A, Barrat F, Flavell R, Gorelick F, Husain S, Mehal W. TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 141: 358–369, 2011.
34. Huang SC, Everts B, Ivanova Y, O’Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O’Neill CM, Yan C, Du H, Abumrad NA, Urban JF Jr, Artyomov MN, Pearce EL, Pearce EJ. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15: 846–855, 2014.
35. Huang W, Booth DM, Cane MC, Chvanov M, Javed MA, Elliott VL, Armstrong JA, Dingsdale H, Cash N, Li Y, Greenhalf W, Mukherjee R, Kaphalia BS, Jaffar M, Petersen OH, Tepikin AV, Sutton R, Criddle DN. Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2_-dependent mitochondrial dysfunction and acute pancreatitis. Gut 63: 1313–1324, 2014.
36. Ishiyama A, Komaki H, Saito T, Saito Y, Nakagawa E, Sugai K, Itagaki Y, Matsuzaki K, Nakura M, Nishino I, Goto Y, Sasaki M. Unusual exocrine complication of pancreatitis in mitochondrial disease. Brain Dev 35: 654–659, 2013.
37. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, Eisenbarth SC, Florquin S, Flavell RA, Leemans JC, Sutterwala FS. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci USA 106: 20388–20393, 2009.
38. Jeyarajah DR, Kielar M, Gokaslan ST, Lindberg G, Lu CY. Fas deficiency exacerbates cerulein-induced pancreatitis. J Invest Surg 16: 325–333, 2003.
39. Kaiser AM, Saluja AK, Sengupta A, Saluja M, Steer ML. Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis. Am J Physiol Cell Physiol 269: C1295–C1304, 1995.
40. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22: 685–708, 2000.
41. Kang R, Zhang Q, Hou W, Yan Z, Chen R, Bonaroti J, Bansal P, Billiar TR, Tsung A, Wang Q, Bartlett DL, Whitcomb DC, Chang EB, Zhu X, Wang H, Lu B, Tracey KJ, Cao L, Fan XG, Lotze MT, Zeh HJ, 3rd, Tang D. Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology 146: 1097–1107, 2014.
42. Kaphalia BS, Bhopale KK, Kondraganti S, Wu H, Boor PJ, Ansari GA. Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol. Toxicol Appl Pharmacol 246: 154–162, 2010.
43. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25: 1939–1948, 2013.
44. Kawakami A, Nakashima K, Tamai M, Nakamura H, Iwanaga N, Fujikawa K, Aramaki T, Arima K, Iwamoto N, Ichinose K, Kamachi M, Ida H, Origuchi T, Eguchi K. Toll-like receptor in salivary glands from patients with Sjogren’s syndrome: functional analysis by human salivary gland cell line. J Rheumatol 34: 1019–1026, 2007.
45. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM. Non-canonical inflammasome activation targets caspase-11. Nature 479: 117–121, 2011.
46. Kempuraj D, Twait EC, Williard DE, Yuan Z, Meyerholz DK, Samuel I. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice. PloS one 8: e56866, 2013.
47. Keyel PA. How is inflammation initiated? Individual influences of IL-1, IL-18 and HMGB 1. Cytokine 69: 136–145, 2014.
48. Kuhny M, Hochdorfer T, Ayata C, Idzko M, Huber M. CD39 is a negative regulator of P2X7-mediated inflammatory cell death in mast cells (Abstract). Cell Comm Signal 12: 40, 2014.
49. Kunzli BM, Nuhn P, Enjyoji K, Banz Y, Smith RN, Csizmadia E, Schuppan D, Berberat PO, Friess H, Robson SC. Disordered pancreatic inflammatory responses and inhibition of fibrosis in CD39-null mice. Gastroenterology 134: 292–305, 2008.
50. Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell 157: 1013–1022, 2014.
51. Lamkanfi M, Sarkar A, Vande Walle L, Vitari AC, Amer AO, Wewers MD, Tracey KJ, Kanneganti TD, Dixit VM. Inflammasomedependent release of the alarmin HMGB1 in endotoxemia. J Immunol 185: 4385–4392, 2010.
52. Lefrancais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP, Cayrol C. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci USA 109: 1673–1678, 2012.
53. Li N, Wu X, Holzer RG, Lee JH, Todoric J, Park EJ, Ogata H, Gukovskaya AS, Gukovsky I, Pizzo DP, VandenBerg S, Tarin D, Atay C, Arkan MC, Deerinck TJ, Moscat J, Diaz-Meco M, Dawson D, Erkan M, Kleeff J, Karin M. Loss of acinar cell IKKalpha triggers spontaneous pancreatitis in mice. J Clin Invest 123: 2231–2243, 2013.
54. Luthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P, Lavelle EC, Martin SJ. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31: 84–98, 2009.
55. Malleo G, Mazzon E, Genovese T, Di Paola R, Muia C, Centorrino T, Siriwardena AK, Cuzzocrea S. Etanercept attenuates the development of cerulein-induced acute pancreatitis in mice: a comparison with TNF-alpha genetic deletion. Shock 27: 542–551, 2007.
56. Marrache F, Tu SP, Bhagat G, Pendyala S, Osterreicher CH, Gordon S, Ramanathan V, Penz-Osterreicher M, Betz KS, Song Z, Wang TC. Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology 135: 1277–1287, 2008.
57. Martin BN, Wang C, Willette-Brown J, Herjan T, Gulen MF, Zhou H, Bulek K, Franchi L, Sato T, Alnemri ES, Narla G, Zhong XP, Thomas J, Klinman D, Fitzgerald KA, Karin M, Nunez G, Dubyak G, Hu Y, Li X. IKKalpha negatively regulates ASC-dependent inflammasome activation (Abstract). Nat Commun 5: 4977, 2014.
58. McGettrick AF, O’Neill LA. How metabolism generates signals during innate immunity and inflammation. J Biol Chem 288: 22893–22898, 2013.
59. McGettrick AF, O’Neill LA. NLRP3 and IL-1beta in macrophages as critical regulators of metabolic diseases. Diabetes Obesity Metab 15, Suppl 3: 19–25, 2013.
60. Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, Olefsky JM, Brenner DA, Seki E. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139: 323–334, 2010.
61. Nakamichi I, Habtezion A, Zhong B, Contag CH, Butcher EC, Omary MB. Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest 115: 3007–3014, 2005.
62. Navina S, Acharya C, DeLany JP, Orlichenko LS, Baty CJ, Shiva SS, Durgampudi C, Karlsson JM, Lee K, Bae KT, Furlan A, Behari J, Liu S, McHale T, Nichols L, Papachristou GI, Yadav D, Singh VP. Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci Trans Med 3: 107–110, 2011.
63. Norman J, Franz M, Messina J, Riker A, Fabri PJ, Rosemurgy AS, Gower WR Jr. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 117: 648–655, 1995.
64. Norman JG, Fink G, Franz M, Guffey J, Carter G, Davison B, Sexton C, Glaccum M. Active interleukin-1 receptor required for maximal progression of acute pancreatitis. Ann Surg 223: 163–169, 1996.
65. Norman JG, Fink GW, Messina J, Carter G, Franz MG. Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis. Surgery 120: 515–521, 1996.
66. Norman JG, Fink GW, Sexton C, Carter G. Transgenic animals demonstrate a role for the IL-1 receptor in regulating IL-1beta gene expression at steady-state and during the systemic stress induced by acute pancreatitis. J Surg Res 63: 231–236, 1996.
67. O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493: 346–355, 2013.
68. Ouziel R, Gustot T, Moreno C, Arvanitakis M, Degre D, Trepo E, Quertinmont E, Vercruysse V, Demetter P, Le Moine O, McKenzie AN, Delhaye M, Deviere J, Lemmers A. The ST2 pathway is involved in acute pancreatitis: a translational study in humans and mice. Am J Pathol 180: 2330–2339, 2012.
69. Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18: 1279–1285, 2012.
70. Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 32: 742–747, 2000.
71. Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 142: 1100–1101 e1102, 2012.
72. Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, Barrieau M, Min SY, Kurt-Jones EA, Szabo G. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 122: 3476–3489, 2012.
73. Pini M, Sennello JA, Cabay RJ, Fantuzzi G. Effect of diet-induced obesity on acute pancreatitis induced by administration of interleukin-12 plus interleukin-18 in mice. Obesity 18: 476–481, 2010.
74. Qu WM, Miyazaki T, Terada M, Okada K, Mori S, Kanno H, Nose M. A novel autoimmune pancreatitis model in MRL mice treated with polyinosinic:polycytidylic acid. Clin Exp Immunol 129: 27–34, 2002.
75. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Muller- Fielitz H, Pokorna B, Vollbrandt T, Stolting I, Nadrowitz R, Okun JG, Offermanns S, Schwaninger M. The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages (Abstract). Nat Comm 5: 3944, 2014.
76. Rau B, Paszkowski A, Lillich S, Baumgart K, Moller P, Beger HG. Differential effects of caspase-1/interleukin-1beta-converting enzyme on acinar cell necrosis and apoptosis in severe acute experimental pancreatitis. Lab Invest 81: 1001–1013, 2001.
77. Ren JD, Ma J, Hou J, Xiao WJ, Jin WH, Wu J, Fan KH. Hydrogenrich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice (Abstract). Mediat Inflamm 2014: 930894, 2014.
78. Sah RP, Dudeja V, Dawra RK, Saluja AK. Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice. Gastroenterology 144: 1076–1085, 2013.
79. Sawa H, Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Nakajima T, Kuroda Y. Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis. World J Gastroenterol 12: 7666–7670, 2006.
80. Scheuplein F, Schwarz N, Adriouch S, Krebs C, Bannas P, Rissiek B, Seman M, Haag F, Koch-Nolte F. NAD+ and ATP released from injured cells induce P2X7-dependent shedding of CD62L and externalization of phosphatidylserine by murine T cells. J Immunol 182: 2898–2908, 2009.
81. Schneider A, Haas SL, Hildenbrand R, Siegmund S, Reinhard I, Nakovics H, Singer MV, Feick P. Enhanced expression of interleukin- 18 in serum and pancreas of patients with chronic pancreatitis. World J Gastroenterol 12: 6507–6514, 2006.
82. Sendler M, Dummer A, Weiss FU, Kruger B, Wartmann T, Scharffetter-Kochanek K, van Rooijen N, Malla SR, Aghdassi A, Halangk W, Lerch MM, Mayerle J. Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut 62: 430–439, 2013.
83. Sennello JA, Fayad R, Pini M, Gove ME, Ponemone V, Cabay RJ, Siegmund B, Dinarello CA, Fantuzzi G. Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice. Proc Natl Acad Sci USA 105: 8085–8090, 2008.
84. Sesti-Costa R, Silva GK, Proenca-Modena JL, Carlos D, Silva ML, Alves-Filho JC, Arruda E, Liew FY, Silva JS. The IL-33/ST2 pathway controls coxsackievirus B5-induced experimental pancreatitis. J Immunol 191: 283–292, 2013.
85. Sharif R, Dawra R, Wasiluk K, Phillips P, Dudeja V, Kurt-Jones E, Finberg R, Saluja A. Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice. Gut 58: 813–819, 2009.
86. Shugrue CA, Alexandre M, de Villalvilla AD, Kolodecik TR, Young LH, Gorelick FS, Thrower EC. Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. Am J Physiol Gastrointest Liver Physiol 303: G723–G732, 2012.
87. Silva MF, Aires CC, Luis PB, Ruiter JP, LIJ, Duran M, Wanders RJ, Tavares de Almeida I. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inher Metab Dis 31: 205–216, 2008.
88. Tein I, Christodoulou J, Donner E, McInnes RR. Carnitine palmitoyltransferase II deficiency: a new cause of recurrent pancreatitis. J Pediatr 124: 938–940, 1994.
89. Tsuji Y, Watanabe T, Kudo M, Arai H, Strober W, Chiba T. Sensing of commensal organisms by the intracellular sensor NOD1 mediates experimental pancreatitis. Immunity 37: 326–338, 2012.
90. Ueno N, Kashiwamura S, Ueda H, Okamura H, Tsuji NM, Hosohara K, Kotani J, Marukawa S. Role of interleukin 18 in nitric oxide production and pancreatic damage during acute pancreatitis. Shock 24: 564–570, 2005.
91. Vonlaufen A, Spahr L, Apte MV, Frossard JL. Alcoholic pancreatitis: a tale of spirits and bacteria. World J Gastrointest Pathophysiol 5: 82–90, 2014.
92. Watanabe A, Sohail MA, Gomes DA, Hashmi A, Nagata J, Sutterwala FS, Mahmood S, Jhandier MN, Shi Y, Flavell RA, Mehal WZ. Inflammasome- mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 296: G1248–G1257, 2009.
93. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12: 408–415, 2011.
94. Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, Smith B, Banks PA, Conwell DL. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 9: 710–717, 2011.
95. Wu LH, Huang CC, Adhikarakunnathu S, San Mateo LR, Duffy KE, Rafferty P, Bugelski P, Raymond H, Deutsch H, Picha K, Ward CK, Alexoupolou L, Flavell RA, Mbow ML, Susulic VS. Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice. Metab Clin Exp 61: 1633–1645, 2012.
96. Xu J, Jiang Y, Wang J, Shi X, Liu Q, Liu Z, Li Y, Scott MJ, Xiao G, Li S, Fan L, Billiar TR, Wilson MA, Fan J. Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis. Cell Death Differ 21: 1229–1239, 2014.
97. Xue J, Habtezion A. Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition. J Clin Invest 124: 437–447, 2014.
98. Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba R, Savitsky D, Ronfani L, Akira S, Bianchi ME, Honda K, Tamura T, Kodama T, Taniguchi T. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462: 99–103, 2009.
99. Yasuda T, Ueda T, Takeyama Y, Shinzeki M, Sawa H, Nakajima T, Ajiki T, Fujino Y, Suzuki Y, Kuroda Y. Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis. Pancreas 33: 359–363, 2006.
100. Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci USA 111: 15514–15519, 2014.
101. Zuhl M, Dokladny K, Mermier C, Schneider S, Salgado R, Moseley P. The effects of acute oral glutamine supplementation on exerciseinduced gastrointestinal permeability and heat shock protein expression in peripheral blood mononuclear cells. Cell Stress Chaperones 20: 85–93, 2015.