Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis

Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis. Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis. Pancreatitis has been associated with genetic factors, gallstones, and alcohol abuse. The current paradigm is that pancreatitis is initiated by acinar cell injury, leading to parenchymal necrosis and inflammation, which are the main pathologic features of the disease. It is believed that chronic pancreatitis (CP) results from repetitive subclinical or clinically evident bouts of acute pancreatitis (AP), or can develop without prior AP.1Peery A.F. Dellon E.S. Lund J. et al.Burden of gastrointestinal disease in the United States: 2012 update.Gastroenterology. 2012; 143 (e1−e3): 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2Pandol S.J. Saluja A.K. Imrie C.W. et al.Acute pancreatitis: bench to the bedside.Gastroenterology. 2007; 132 (Erratum: 133:1056): 1127-1151Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 3Whitcomb D.C. Genetic risk factors for pancreatic disorders.Gastroenterology. 2013; 144: 1292-1302Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar AP is a leading cause for gastrointestinal-related hospital admissions, with gallstones as a frequent etiologic factor. Although AP is most commonly mild to moderate in severity, as many as 30% of patients with severe disease associated with persistent multi-organ dysfunction die.1Peery A.F. Dellon E.S. Lund J. et al.Burden of gastrointestinal disease in the United States: 2012 update.Gastroenterology. 2012; 143 (e1−e3): 1179-1187Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2Pandol S.J. Saluja A.K. Imrie C.W. et al.Acute pancreatitis: bench to the bedside.Gastroenterology. 2007; 132 (Erratum: 133:1056): 1127-1151Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 3Whitcomb D.C. Genetic risk factors for pancreatic disorders.Gastroenterology. 2013; 144: 1292-1302Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar The pathophysiology of severe AP with multi-organ dysfunction is poorly understood. For many years, researchers believed that AP, and particularly severe pancreatitis, resulted from activation of digestive enzymes within the pancreas.2Pandol S.J. Saluja A.K. Imrie C.W. et al.Acute pancreatitis: bench to the bedside.Gastroenterology. 2007; 132 (Erratum: 133:1056): 1127-1151Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 4Sah R.P. Dawra R.K. Saluja A.K. New insights into the pathogenesis of pancreatitis.Curr Opin Gastroenterol. 2013; 29: 523-530Crossref PubMed Scopus (128) Google Scholar Indeed, patients with hereditary pancreatitis carry mutations in genes encoding for digestive enzymes.3Whitcomb D.C. Genetic risk factors for pancreatic disorders.Gastroenterology. 2013; 144: 1292-1302Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar However, these patients develop recurrent attacks and have a high risk of developing CP rather than severe AP. There is now evidence that the systemic complications associated with AP result from uncontrolled or deregulated activation of the immune system.5Gukovsky I. Li N. Todoric J. et al.Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer.Gastroenterology. 2013; 144: 1199-1209 e4Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 6Habtezion A. Inflammation in acute and chronic pancreatitis.Curr Opin Gastroenterol. 2015; 31: 395-399Crossref PubMed Scopus (87) Google Scholar, 7Phillip V. Steiner J.M. Algul H. 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Karim S.A. Foth M. et al.CXCR2 inhibition suppresses acute and chronic pancreatic inflammation.J Pathol. 2015; 237: 85-97Crossref PubMed Google Scholar, 14Xue J. Habtezion A. Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition.J Clin Invest. 2014; 124: 437-447Crossref PubMed Scopus (54) Google Scholar, 15Zhang H. Neuhofer P. Song L. et al.IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality.J Clin Invest. 2013; 123: 1019-1031Crossref PubMed Scopus (182) Google Scholar), no drugs have been approved by the Food and Drug Administration for treatment of AP or CP, and morbidity remains high. There is, therefore, an urgent need to elucidate the mechanisms that initiate and promote pancreatitis. Autophagy is the major catabolic process by which cells eliminate damaged, defective, or unwanted cytoplasmic organelles, long-lived proteins, and lipids, and recycle their constituents for energy and biogenesis needs. Hundreds of studies on the functions and mechanisms of autophagy during the last decade revealed its key homeostatic roles in metabolic adaptation, "quality control" of intracellular organelles, and differentiation and development. Deregulation of autophagy has been associated with the pathogenesis of many diseases, including neurodegenerative and inflammatory disorders and cancer. The physiologic and pathologic roles of autophagy in mammalian cells have been extensively reviewed.16Parzych K.R. Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation.Antioxid Redox Signal. 2014; 20: 460-473Crossref PubMed Scopus (873) Google Scholar, 17Choi A.M. Ryter S.W. Levine B. Autophagy in human health and disease.N Engl J Med. 2013; 368: 651-662Crossref PubMed Scopus (860) Google Scholar, 18Klionsky D.J. Abdelmohsen K. Abe A. et al.Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).Autophagy. 2016; 12: 1-222Crossref PubMed Scopus (3634) Google Scholar, 19Kroemer G. Autophagy: a druggable process that is deregulated in aging and human disease.J Clin Invest. 2015; 125: 1-4Crossref PubMed Scopus (191) Google Scholar Inflammation eliminates cells that have been damaged during injury or infection and initiates tissue repair. Efficient development and resolution of the inflammatory response and restoration of tissue homeostasis depend on coordinated interactions between neutrophils, macrophages, and other types of immune cells, controlled by secreted mediators, such as cytokines and chemokines. Cytokines and chemokines recruit leukocytes and other immune cells to the inflamed pancreas,5Gukovsky I. Li N. Todoric J. et al.Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer.Gastroenterology. 2013; 144: 1199-1209 e4Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 20Norman J. The role of cytokines in the pathogenesis of acute pancreatitis.Am J Surg. 1998; 175: 76-83Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar as demonstrated by various blockade approaches.5Gukovsky I. Li N. Todoric J. et al.Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer.Gastroenterology. 2013; 144: 1199-1209 e4Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 6Habtezion A. Inflammation in acute and chronic pancreatitis.Curr Opin Gastroenterol. 2015; 31: 395-399Crossref PubMed Scopus (87) Google Scholar, 9Bhatia M. Hegde A. Treatment with antileukinate, a CXCR2 chemokine receptor antagonist, protects mice against acute pancreatitis and associated lung injury.Regul Pept. 2007; 138: 40-48Crossref PubMed Scopus (45) Google Scholar, 10Frossard J.L. Lenglet S. Montecucco F. et al.Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury.J Clin Pathol. 2011; 64: 387-393Crossref PubMed Scopus (35) Google Scholar, 11Hoque R. Farooq A. Ghani A. et al.Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.Gastroenterology. 2014; 146: 1763-1774Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 12Huang L. Ma J. Tang Y. et al.siRNA-based targeting of fractalkine overexpression suppresses inflammation development in a severe acute pancreatitis rat model.Int J Mol Med. 2012; 30: 514-520Crossref PubMed Scopus (9) Google Scholar, 13Steele C.W. Karim S.A. Foth M. et al.CXCR2 inhibition suppresses acute and chronic pancreatic inflammation.J Pathol. 2015; 237: 85-97Crossref PubMed Google Scholar, 14Xue J. Habtezion A. Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition.J Clin Invest. 2014; 124: 437-447Crossref PubMed Scopus (54) Google Scholar, 15Zhang H. Neuhofer P. Song L. et al.IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality.J Clin Invest. 2013; 123: 1019-1031Crossref PubMed Scopus (182) Google Scholar Deregulated autophagy and unresolved inflammation contribute to development of pancreatitis. Disordered acinar cell autophagy has been implicated in disease initiation, whereas the severity of AP is largely determined by whether the inflammatory response resolves or amplifies, leading to multi-organ dysfunction. Persistent low-grade inflammation is a characteristic of CP and an important factor in the development of pancreatic ductal adenocarcinoma. We review the roles of autophagy and inflammation in pancreatitis, the mechanisms of their deregulation, and the pathways that link these processes. We discuss findings from in vitro studies, mouse models of AP and CP, and patients. We identify gaps in our knowledge and delineate perspective directions for research. Autophagy is a collective term for several pathways through which cytoplasmic materials are delivered to the lysosome and degraded by lysosomal hydrolases.16Parzych K.R. Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation.Antioxid Redox Signal. 2014; 20: 460-473Crossref PubMed Scopus (873) Google Scholar, 17Choi A.M. Ryter S.W. Levine B. Autophagy in human health and disease.N Engl J Med. 2013; 368: 651-662Crossref PubMed Scopus (860) Google Scholar, 18Klionsky D.J. Abdelmohsen K. Abe A. et al.Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).Autophagy. 2016; 12: 1-222Crossref PubMed Scopus (3634) Google Scholar The resultant degradation products, such as amino and fatty acids, are recycled back to the cytosol through transporters and permeases.16Parzych K.R. Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation.Antioxid Redox Signal. 2014; 20: 460-473Crossref PubMed Scopus (873) Google Scholar, 17Choi A.M. Ryter S.W. Levine B. Autophagy in human health and disease.N Engl J Med. 2013; 368: 651-662Crossref PubMed Scopus (860) Google Scholar The types of autophagy differ by how the cargo is delivered to lysosomes. Macroautophagy requires de novo formation of double-membraned structures termed autophagosomes, which sequester cargo and ultimately fuse with lysosomes to form autolysosomes, where degradation occurs (Figure 1). In chaperone-mediated autophagy, cytosolic proteins carrying a specific sequence motif bind to a receptor on the lysosome and are delivered into the lysosomal lumen. Microautophagy is mediated by direct lysosomal engulfment of small cytoplasmic components. In crinophagy, secretory vesicles fuse with the lysosomes and are degraded by lysosomal hydrolases21Weckman A. Di Ieva A. Rotondo F. et al.Autophagy in the endocrine glands.J Mol Endocrinol. 2014; 52: R151-R163Crossref PubMed Scopus (54) Google Scholar; this process was noted in pancreatitis decades ago,22Koike H. Steer M.L. Meldolesi J. Pancreatic effects of ethionine: blockade of exocytosis and appearance of crinophagy and autophagy precede cellular necrosis.Am J Physiol. 1982; 242: G297-G307Crossref PubMed Google Scholar but the fusion mechanism remains unknown. Macroautophagy (hereafter referred to as autophagy) is the best studied form of autophagy and the only one examined in normal exocrine pancreas and in pancreatitis. It starts with the formation of autophagosomes, which in mammalian cells derive from various donor membranes, including the endoplasmic reticulum (ER), Golgi complex, or the plasma membrane. The process begins with the formation of so-called isolation membrane, or phagophore, followed by its elongation and closure to form the mature autophagosome, a globular double-membraned organelle (Figure 1). These steps are mediated by hierarchically recruited complexes of evolutionary conserved ATG (autophagy-related) proteins. Autophagy initiation is controlled by ULK1/ATG1-mediated complex, followed by the formation of another multiprotein complex involving phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3 or VPS34) and beclin1, which nucleates the phagophore. Phagophore expansion and elongation are controlled by the ubiquitin-like conjugation systems involving the ATG5−ATG12−ATG16 complex and microtubule-associated protein 1 light chain 3α (LC3). LC3, the mammalian paralog of yeast ATG8, is necessary for phagophore closure; during this process, its cytosolic form (LC3-I) is lipidated to become LC3-II, which specifically translocates to the autophagosome membrane. Autophagosomes fuse with late endosomes and, ultimately, lysosomes, forming single-membraned autolysosomes, where cargo breakdown occurs. Recent studies have advanced our knowledge of the lysosome as a dynamic organelle that regulates autophagy to meet the cell's degradation and recycling needs.23Ferguson S.M. Beyond indigestion: emerging roles for lysosome-based signaling in human disease.Curr Opin Cell Biol. 2015; 35: 59-68Crossref PubMed Scopus (43) Google Scholar A master regulator of lysosomal biogenesis, the transcription factor EB coordinates the expression of lysosomal proteins and proteins involved in autophagy.24Settembre C. Fraldi A. Medina D.L. et al.Signals from the lysosome: a control centre for cellular clearance and energy metabolism.Nat Rev Mol Cell Biol. 2013; 14: 283-296Crossref PubMed Scopus (948) Google Scholar Formation of autophagosomes and autolysosomes are key steps in autophagy. Autophagosomes sequester cargo (eg, organelles) destined for degradation. Their luminal pH is neutral and they do not contain hydrolases. In contrast, the lumen of the autolysosome is acidic and contains multiple hydrolases. Because LC3-II is almost exclusively associated with the autophagosome's membranes, it is commonly used to monitor autophagy.18Klionsky D.J. Abdelmohsen K. Abe A. et al.Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).Autophagy. 2016; 12: 1-222Crossref PubMed Scopus (3634) Google Scholar LC3-II remains present on early autolysosome's membrane until being degraded; autolysosomes, but not autophagosomes, also bear on their surface lysosomal markers, such as lysosome-associated membrane proteins (LAMPs). Recent studies25Nakamura S. Yoshimori T. New insights into autophagosome-lysosome fusion.J Cell Sci. 2017; 130: 1209-1216Crossref PubMed Scopus (246) Google Scholar have demonstrated the complexity of autophagosome transport along microtubules to the site of late endosomes and lysosomes, which are predominantly located in the perinuclear region, and of the fusion process. Macroautophagy can be selective and nonselective.26Dengjel J. Abeliovich H. Roles of mitophagy in cellular physiology and development.Cell Tissue Res. 2017; 367: 95-109Crossref PubMed Scopus (2) Google Scholar, 27Mizumura K. 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Selective autophagy is initiated through specific receptors on the cellular component destined for degradation, which interact with LC3 (or functionally equivalent protein GABARAP) to deliver this component to autophagosomes. One receptor is sequestosome 1 (SQSTM1, also known as p62), a multi-domain protein that serves as signaling scaffold and chaperone for polyubiquitinated proteins; it regulates a variety of cellular processes, including autophagy and oxidative stress.16Parzych K.R. Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation.Antioxid Redox Signal. 2014; 20: 460-473Crossref PubMed Scopus (873) Google Scholar, 17Choi A.M. Ryter S.W. Levine B. Autophagy in human health and disease.N Engl J Med. 2013; 368: 651-662Crossref PubMed Scopus (860) Google Scholar, 29Katsuragi Y. Ichimura Y. 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Beyond starvation: an update on the autophagic machinery and its functions.J Mol Cell Cardiol. 2016; 95: 2-10Abstract Full Text Full Text PDF PubMed Google Scholar In normal physiologic conditions, autophagic flux (ie, turnover of autophagic vacuoles, from the formation of autophagosomes to cargo degradation in autolysosomes) is efficient, and there is no vacuole accumulation. Accumulation of autophagosomes could be via increased formation or defective fusion with lysosomes, whereas accumulation of autolysosomes indicates defective lysosomal degradation. p62 is specifically degraded by autophagy and is kept at a low level in normal conditions. Thus, excessive cell vacuolization and accumulation of p62 (especially together with LC3-II) are markers of impaired autophagy. Mouse exocrine pancreas has a high basal level of autophagy, which is activated in response to starvation to a greater extent than in liver, kidney, heart, or endocrine pancreas.30Mizushima N. Yamamoto A. 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Disruption of genes encoding proteins that mediate autophagosome formation (ATG5 or ATG7) or lysosomal function (LAMP2) causes autophagy blockade or impairment in the pancreas, resulting in severe acinar cell degeneration, exocrine pancreas atrophy, fibrosis, and inflammation.32Diakopoulos K.N. Lesina M. Wormann S. et al.Impaired autophagy induces chronic atrophic pancreatitis in mice via sex- and nutrition-dependent processes.Gastroenterology. 2015; 148: 626-638 e17Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 33Gukovsky I. Gukovskaya A.S. Impaired autophagy triggers chronic pancreatitis: lessons from pancreas-specific atg5 knockout mice.Gastroenterology. 2015; 148: 501-505Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 34Antonucci L. Fagman J.B. 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Malla S.R. et al.Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis: LAMP-2 deficient mice develop pancreatitis.Cell Mol Gastroenterol Hepatol. 2015; 1: 678-694Abstract Full Text Full Text PDF PubMed Google Scholar We only review acinar cell autophagy and its role in pancreatitis, as there is little information on the effects of pancreatitis on autophagy in other cell types, such as inflammatory or stellate cells. A prominent feature of pancreatitis is the accumulation of large vacuoles in acinar cells.31Gukovskaya A.S. Gukovsky I. Autophagy and pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G993-G1003Crossref PubMed Scopus (91) Google Scholar, 36Helin H. Mero M. Markkula H. et al.Pancreatic acinar ultrastructure in human acute pancreatitis.Virchows Arch A Pathol Anat Histol. 1980; 387: 259-270Crossref PubMed Google Scholar, 37Mareninova O.A. Hermann K. 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