Pathogenesis of autoimmune and hereditary pancreatitis with a focus on neutrophil granulocytes and neutrophil serine proteases

Abstract

Hereditary and autoimmune pancreatitis are two rare forms of inflammatory pancreatic disorders. Both share similarities with acute, acute recurrent, and chronic pancreatitis. Regarding their pathogenesis, the premature activation of the digestive protease trypsinogen and the infiltration of inflammatory cells such as polymorphonuclear leukocytes and macrophages into the pancreas are highly relevant and can reciprocally amplify inflammation. Neutrophil serine proteases are the main components of neutrophil granulocytes and have different pro-inflammatory effects in many diseases. However, their role in pancreatitis is still limited. This section focuses on known findings regarding the role of this group of enzymes in hereditary and autoimmune pancreatitis.

Keywords

Hereditary pancreatitis / autoimmune pancreatitis / neutrophil serine proteases / cathepsin C

References

[1] Peery AF,Murphy CC.Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018.Gastroenterology2019;156:254-272.e11 PMCID:PMC6689327

[2] Wiese ML,von Rheinbaben S.Identification of early predictors for infected necrosis in acute pancreatitis.BMC Gastroenterol2022;22:405 PMCID:PMC9440524

[3] Weiss FU,Lerch MM.Acute pancreatitis: genetic risk and clinical implications.J Clin Med2021;10:190 PMCID:PMC7825757

[4] Gorry MC,Furey W.Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis.Gastroenterology1997;113:1063-8

[5] Whitcomb DC.Genetic risk factors for pancreatic disorders.Gastroenterology2013;144:1292-302 PMCID:PMC3684061

[6] Girodon E,Chen JM.Clinical interpretation of PRSS1 variants in patients with pancreatitis.Clin Res Hepatol Gastroenterol2021;45:101497

[7] Comfort MW.Pedigree of a family with hereditary chronic relapsing pancreatitis.Gastroenterology1952;21:54-63

[8] Whitcomb DC,Preston RA.Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.Nat Genet1996;14:141-5

[9] Coté GA,Slivka A.North American Pancreatitis Study GroupAlcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis.Clin Gastroenterol Hepatol2011;9:266-73; quiz e27 PMCID:PMC3043170

[10] Rebours V,Schnee M.The natural history of hereditary pancreatitis: a national series.Gut2009;58:97-103

[11] Howes N,Greenhalf W.European Registry of Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC)Clinical and genetic characteristics of hereditary pancreatitis in Europe.Clin Gastroenterol Hepatol2004;2:252-61

[12] Sultan M,Venkatasubramani N.Genetic prevalence and characteristics in children with recurrent pancreatitis.J Pediatr Gastroenterol Nutr2012;54:645-50

[13] Sahin-Tóth M.Human cationic trypsinogen. Role of Asn-21 in zymogen activation and implications in hereditary pancreatitis.J Biol Chem2000;275:22750-5

[14] Teich N,Kukor Z.Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2).Hum Mutat2004;23:22-31

[15] Kereszturi E,Kukor Z.Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism.Hum Mutat2009;30:575-82 PMCID:PMC2663013

[16] Witt H,Hennies HC.Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.Nat Genet2000;25:213-6

[17] Schneider A.Serine protease inhibitor kazal type 1 mutations and pancreatitis.Clin Lab Med2005;25:61-78

[18] Király O,Witt H.Signal peptide variants that impair secretion of pancreatic secretory trypsin inhibitor (SPINK1) cause autosomal dominant hereditary pancreatitis.Hum Mutat2007;28:469-76 PMCID:PMC2765331

[19] Szmola R.Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht’s enzyme Y.Proc Natl Acad Sci USA2007;104:11227-32 PMCID:PMC2040881

[20] Rosendahl J,Szmola R.Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.Nat Genet2008;40:78-82 PMCID:PMC2650829

[21] Anderson MP,Gregory RJ,Welsh MJ.Generation of cAMP-activated chloride currents by expression of CFTR.Science1991;251:679-82

[22] Quinton PM.Chloride impermeability in cystic fibrosis.Nature1983;301:421-2

[23] Reddy MM.Selective activation of cystic fibrosis transmembrane conductance regulator CL- and HCO₃- conductances.JOP2001;2(4 Suppl):212-8

[24] Stutts MJ,Olsen JC.CFTR as a cAMP-dependent regulator of sodium channels.Science1995;269:847-50

[25] Durno C,Zielenski J,Tsui LC.Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis.Gastroenterology2002;123:1857-64

[26] Ooi CY,Cipolli M.Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.Gastroenterology2011;140:153-61

[27] Behrendorff N,Schwiening C.Protons released during pancreatic acinar cell secretion acidify the lumen and contribute to pancreatitis in mice.Gastroenterology2010;139:1711-20, 1720.e1

[28] Pallagi P,Rakonczay Z Jr.Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl^⁻ channels and luminal anion exchangers.Gastroenterology2011;141:2228-2239.e6

[29] Hui DY.Carboxyl ester lipase: structure-function relationship and physiological role in lipoprotein metabolism and atherosclerosis.J Lipid Res2002;43:2017-30

[30] Fjeld K,Lasher D.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet2015;47:518-22 PMCID:PMC5321495

[31] Fjeld K,Brekke RS.The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice.Pancreatology2022;22:1099-111

[32] El Jellas K,Haldorsen IS.Two new mutations in the CEL gene causing diabetes and hereditary pancreatitis: how to correctly identify MODY8 cases.J Clin Endocrinol Metab2022;107:e1455-e1466 PMCID:PMC8947231

[33] Witt H,Rosendahl J.Variants in CPA1 are strongly associated with early onset chronic pancreatitis.Nat Genet2013;45:1216-20 PMCID:PMC3909499

[34] Moore PC,Chamberlain CE.Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma.J Clin Invest2019;129:4676-81 PMCID:PMC6819098

[35] SARLES H,MURATORE R.Chronic inflammatory sclerosis of the pancreas-an autonomous pancreatic disease?.Am J Dig Dis1961;6:688-98

[36] Yoshida K,Takeuchi T,Shiratori K.Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis.Dig Dis Sci1995;40:1561-8

[37] Schneider A,Weiss C.Prevalence and incidence of autoimmune pancreatitis in the population living in the southwest of Germany.Digestion2017;96:187-98

[38] Kanno A,Okazaki K.Research Committee of Intractable Diseases of the PancreasNationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011.Pancreas2015;44:535-9

[39] Kamisawa T,Inokuma S.Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy.Pancreas2003;27:235-8

[40] Kamisawa T,Giday SA.Clinical profile of autoimmune pancreatitis and its histological subtypes: an international multicenter survey.Pancreas2011;40:809-14

[41] Sandrasegaran K.Imaging in autoimmune pancreatitis and immunoglobulin g4-related disease of the abdomen.Gastroenterol Clin North Am2018;47:603-19

[42] Hart PA,Brugge WR.Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis.Gut2013;62:1771-6 PMCID:PMC3862979

[43] John DS,Krüger B.Deficiency of cathepsin C ameliorates severity of acute pancreatitis by reduction of neutrophil elastase activation and cleavage of E-cadherin.J Biol Chem2019;294:697-707 PMCID:PMC6333881

[44] Ito T,Fujimori N.Characteristics of pancreatic diabetes in patients with autoimmune pancreatitis.J Dig Dis2011;12:210-6

[45] Zamboni G,Capelli P.Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens.Virchows Arch2004;445:552-63

[46] Shinagare S,Deshpande V.Autoimmune pancreatitis: a guide for the histopathologist.Semin Diagn Pathol2012;29:197-204

[47] Ikeura T,Zamboni G.Application of international consensus diagnostic criteria to an Italian series of autoimmune pancreatitis.United European Gastroenterol J2013;1:276-84 PMCID:PMC4040792

[48] Löhr JM,Koczan D.Autoantibodies against the exocrine pancreas in autoimmune pancreatitis: gene and protein expression profiling and immunoassays identify pancreatic enzymes as a major target of the inflammatory process.Am J Gastroenterol2010;105:2060-71 PMCID:PMC3099227

[49] Frulloni L,Simone R.Identification of a novel antibody associated with autoimmune pancreatitis.N Engl J Med2009;361:2135-42

[50] Mayerle J,Hegyi E,Lerch MM.Genetics, cell biology, and pathophysiology of pancreatitis.Gastroenterology2019;156:1951-1968.e1 PMCID:PMC6903413

[51] Halangk W,Brandt-Nedelev B.Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis.J Clin Invest2000;106:773-81 PMCID:PMC381392

[52] Saluja A,Saluja M,Meldolesi J.Subcellular redistribution of lysosomal enzymes during caerulein-induced pancreatitis.Am J Physiol1987;253:G508-16

[53] Ohmuraya M.Roles of serine protease inhibitor Kazal type 1 (SPINK1) in pancreatic diseases.Exp Anim2011;60:433-44

[54] Wartmann T,Kähne T.Cathepsin L inactivates human trypsinogen, whereas cathepsin L-deletion reduces the severity of pancreatitis in mice.Gastroenterology2010;138:726-37 PMCID:PMC2941736

[55] Aghdassi AA,Sendler M.Cathepsin D regulates cathepsin B activation and disease severity predominantly in inflammatory cells during experimental pancreatitis.J Biol Chem2018;293:1018-29 PMCID:PMC5777244

[56] Gukovsky I,Blinman TA,Pandol SJ.Early NF-kappaB activation is associated with hormone-induced pancreatitis.Am J Physiol1998;275:G1402-14

[57] Sendler M,Golchert J.Cathepsin B-mediated activation of trypsinogen in endocytosing macrophages increases severity of pancreatitis in mice.Gastroenterology2018;154:704-718.e10 PMCID:PMC6663074

[58] Gukovskaya AS,Zaninovic V.Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis.Gastroenterology2002;122:974-84

[59] Abdulla A,Thorlacius H.Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis.J Leukoc Biol2011;90:975-82

[60] Awla D,Syk I,Regnér S.Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.J Leukoc Biol2012;91:711-9

[61] Mcguire M,Thiele D.Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I.Journal of Biological Chemistry1993;268:2458-67

[62] Turk D,Stern I.Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases.EMBO J2001;20:6570-82 PMCID:PMC125750

[63] Adkison AM,Kelley DG.Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis.J Clin Invest2002;109:363-71 PMCID:PMC150852

[64] Mayerle J,Krüger B.Extracellular cleavage of E-cadherin by leukocyte elastase during acute experimental pancreatitis in rats.Gastroenterology2005;129:1251-67

[65] Aghdassi AA,Sendler M.Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis.Sci Rep2019;9:16774 PMCID:PMC6856518

[66] Leppkes M,Hirth S.Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.Nat Commun2016;7:10973 PMCID:PMC4793047

[67] Merza M,Rahman M.Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis.Gastroenterology2015;149:1920-1931.e8

[68] Geisz A.A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation.Nat Commun2018;9:5033 PMCID:PMC6261995

[69] Archer H,Keller J,Bar-Sagi D.A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen.Gastroenterology2006;131:1844-55

[70] Mitsuyama T,Sumimoto K.Comparison of neutrophil infiltration between type 1 and type 2 autoimmune pancreatitis.Pancreatology2015;15:271-80

[71] Marinaccio L,Scioli G.Peptide human neutrophil elastase inhibitors from natural sources: an overview.Int J Mol Sci2022;23:2924 PMCID:PMC8954713

[72] Sjö P.Neutrophil elastase inhibitors: recent advances in the development of mechanism-based and nonelectrophilic inhibitors.Future Med Chem2012;4:651-60

[73] Cao C,Shou S.Ulinastatin protects against LPS-induced acute lung injury by attenuating TLR4/NF-κB pathway activation and reducing inflammatory mediators.Shock2018;50:595-605

[74] Testoni PA,Masci E.Frequency of post-ERCP pancreatitis in a single tertiary referral centre without and with routine prophylaxis with gabexate: a 6-year survey and cost-effectiveness analysis.Dig Liver Dis2006;38:588-95

[75] Cao J.Protective effects of sivelestat in a caerulein-induced rat acute pancreatitis model.Inflammation2013;36:1348-56

[76] Wang H,Tang A,Ma P.Combined effects of sivelestat and resveratrol on severe acute pancreatitis-associated lung injury in rats.Exp Lung Res2014;40:288-97

[77] Dobschuetz E,Messmer K.Inhibition of neutrophil proteinases by recombinant serpin Lex032 reduces capillary no-reflow in ischemia/reperfusion-induced acute pancreatitis.J Pharmacol Exp Ther1999;290:782-8