Neutrophils in ulcerative colitis: a review of selected biomarkers and their potential therapeutic implications

References

• Burisch J, Munkholm P. The epidemiology of inflammatory bowel disease. Scand J Gastroenterol. 2015;50:942–951.
   PubMed Web of Science ®Google Scholar
• Leitner GC, Vogelsang H. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults. World J Gastrointest Pharmacol Ther. 2016;7:5–20.
   PubMedGoogle Scholar
• Bressenot A, Salleron J, Bastien C, et al. Comparing histological activity indexes in UC. Gut. 2015;64:1412–1418.
   PubMed Web of Science ®Google Scholar
• Mosli MH, Feagan BG, Sandborn WJ, et al. Histologic evaluation of ulcerative colitis: a systematic review of disease activity indices. Inflam Bowel Dis. 2014;20:564–575.
   PubMed Web of Science ®Google Scholar
• Riley SA, Mani V, Goodman MJ, et al. Microscopic activity in ulcerative colitis: what does it mean? Gut. 1991;32:174–178.
   PubMed Web of Science ®Google Scholar
• Geboes K, Riddell R, Ost A, et al. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000;47:404–409.
   PubMed Web of Science ®Google Scholar
• Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and validation of the Nancy histological index for UC. Gut. 2015. [Epub ahead of print]. doi:10.1136/gutjnl-2015-31018.
   Google Scholar
• Rosenberg L, Nanda KS, Zenlea T, et al. Histologic markers of inflammation in patients with ulcerative colitis in clinical remission. Clin Gastroenterol Hepatol. 2013;11:991–996.
   PubMed Web of Science ®Google Scholar
• Peyrin-Biroulet L, Bressenot A, Kampman W. Histologic remission: the ultimate therapeutic goal in ulcerative colitis? Clin Gastroenterol Hepatol. 2014;12:929–934.e2.
   PubMed Web of Science ®Google Scholar
• Brannigan AE, O'Connell PR, Hurley H, et al. Neutrophil apoptosis is delayed in patients with inflammatory bowel disease. Shock. 2000;13:361–366.
   PubMed Web of Science ®Google Scholar
• Uddin M, Nong G, Ward J, et al. Prosurvival activity for airway neutrophils in severe asthma. Thorax. 2010;65:684–689.
   PubMed Web of Science ®Google Scholar
• Lampinen M, Sangfelt P, Taha Y, et al. Accumulation, activation, and survival of neutrophils in ulcerative colitis: regulation by locally produced factors in the colon and impact of steroid treatment. Int J Colorectal Dis. 2008;23:939–946.
   PubMed Web of Science ®Google Scholar
• Uddin M, Lau LC, Seumois G, et al. EGF-induced bronchial epithelial cells drive neutrophil chemotactic and anti-apoptotic activity in asthma. PLoS One. 2013;8:e72502.
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–1535.
   PubMed Web of Science ®Google Scholar
• Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 2012;5:354–366.
   PubMed Web of Science ®Google Scholar
• Sorensen OE, Borregaard N. Neutrophil extracellular traps – the dark side of neutrophils. J Clin Invest. 2016;126:1612–1620.
   PubMed Web of Science ®Google Scholar
• Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol. 2014;15:602–611.
   PubMed Web of Science ®Google Scholar
• Uriarte SM, Powell DW, Luerman GC, et al. Comparison of proteins expressed on secretory vesicle membranes and plasma membranes of human neutrophils. J Immunol. 2008;180:5575–5581.
   PubMed Web of Science ®Google Scholar
• Lominadze G, Powell DW, Luerman GC, et al. Proteomic analysis of human neutrophil granules. Mol Cell Proteomics. 2005;4:1503–1521.
   PubMed Web of Science ®Google Scholar
• Rennard SI, Dale DC, Donohue JF, et al. CXCR2 antagonist MK-7123. A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:1001–1011.
   PubMed Web of Science ®Google Scholar
• Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012;42:1097–1103.
   PubMed Web of Science ®Google Scholar
• Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10:593–601.
   PubMed Web of Science ®Google Scholar
• Røseth AG, Schmidt PN, Fagerhol MK. Correlation between faecal excretion of indium-111-labelled granulocytes and calprotectin, a granulocyte marker protein, in patients with inflammatory bowel disease . Scand J Gastroenterol. 1999;34:50–54.
   PubMed Web of Science ®Google Scholar
• Steinbakk M, Naess-Andresen CF, Lingaas E, et al. Antimicrobial actions of calcium binding leucocyte L1 protein, calprotectin. Lancet. 1990;336:763–765.
   PubMed Web of Science ®Google Scholar
• Corbin BD, Seeley EH, Raab A, et al. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science. 2008;319:962–965.
   PubMed Web of Science ®Google Scholar
• Orsi N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals. 2004;17:189–196.
   PubMed Web of Science ®Google Scholar
• Urban CF, Ermert D, Schmid M, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against candida albicans. PLoS Pathogens. 2009;5:e1000639.
   PubMed Web of Science ®Google Scholar
• Viemann D, Strey A, Janning A, et al. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood. 2005;105:2955–2962.
   PubMed Web of Science ®Google Scholar
• Rammes A, Roth J, Goebeler M, et al. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272:9496–9502.
   PubMed Web of Science ®Google Scholar
• Legrand D. Lactoferrin, a key molecule in immune and inflammatory processes. Biochem Cell Biol. 2012;90:252–268.
   PubMed Web of Science ®Google Scholar
• Legrand D, Elass E, Carpentier M, et al. Lactoferrin: a modulator of immune and inflammatory responses. Cell Mol Life Sci. 2005;62:2549–2559.
   PubMed Web of Science ®Google Scholar
• Røseth AG, Fagerhol MK, Aadland E, et al. Assessment of the neutrophil dominating protein calprotectin in feces. A methodologic study. Scand J Gastroenterol. 1992;27:793–798.
   PubMed Web of Science ®Google Scholar
• Carroccio A, Iacono G, Cottone M, et al. Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children. Clin Chem. 2003;49:861–867.
   PubMed Web of Science ®Google Scholar
• Costa F, Mumolo MG, Bellini M, et al. Role of fecal calprotectin as noninvasive marker of intestinal inflammation. Dig Liver Dis. 2003;35:642–647.
   PubMedGoogle Scholar
• Kane SV, Sandborn WJ, Rufo PA, et al. Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation. Am J Gastroenterol. 2003;98:1309–1314.
   PubMed Web of Science ®Google Scholar
• Dolwani S, Metzner M, Wassell JJ, et al. Diagnostic accuracy of fecal calprotectin estimation in prediction of abnormal small bowel radiology. Aliment Pharmacol Ther. 2004;20:615–621.
   PubMed Web of Science ®Google Scholar
• Schoepfer AM, Trummler M, Seeholzer P, et al. Accuracy of four fecal assays in the diagnosis of colitis. Dis Colon Rectum. 2007;50:1697–1706.
   PubMed Web of Science ®Google Scholar
• Schoepfer AM, Trummler M, Seeholzer P, et al. Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis. 2008;14:32–39.
   PubMed Web of Science ®Google Scholar
• von Roon AC, Karamountzos L, Purkayastha S, et al. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol. 2007;102:803–813.
   PubMed Web of Science ®Google Scholar
• Yamamoto T, Shiraki M, Bamba T, et al. Fecal calprotectin and lactoferrin as predictors of relapse in patients with quiescent ulcerative colitis during maintenance therapy. Int J Colorectal Dis. 2014;29:485–491.
   PubMed Web of Science ®Google Scholar
• D'Inca R, Dal Pont E, Di Leo V, et al. Can calprotectin predict relapse risk in inflammatory bowel disease? Am J Gastroenterol. 2008;103:2007–2014.
   PubMed Web of Science ®Google Scholar
• Røseth AG, Aadland E, Jahnsen J, et al. Assessment of disease activity in ulcerative colitis by faecal calprotectin, a novel granulocyte marker protein. Digestion. 1997;58:176–180.
   PubMed Web of Science ®Google Scholar
• Bunn SK, Bisset WM, Main MJ, et al. Fecal calprotectin as a measure of disease activity in childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2001;32:171–177.
   PubMed Web of Science ®Google Scholar
• Langhorst J, Elsenbruch S, Koelzer J, et al. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol. 2008;103:162–169.
   PubMed Web of Science ®Google Scholar
• D'Inca R, Dal Pont E, Di Leo V, et al. Calprotectin and lactoferrin in the assessment of intestinal inflammation and organic disease. Int J Colorectal Dis. 2007;22:429–437.
   PubMed Web of Science ®Google Scholar
• Basso D, Zambon C, Plebani M. Inflammatory bowel diseases: from pathogenesis to laboratory testing. Clin Chem Lab Med. 2014;52:471–481.
   PubMed Web of Science ®Google Scholar
• Menees SB, Powell C, Kurlander J, et al. A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS. Am J Gastroenterol. 2015;110:444–454.
   PubMed Web of Science ®Google Scholar
• Lehmann FS, Burri E, Beglinger C. The role and utility of faecal markers in inflammatory bowel disease. Therap Adv Gastroenterol. 2015;8:23–36.
   PubMed Web of Science ®Google Scholar
• Takashima S, Kato J, Hiraoka S, et al. Evaluation of mucosal healing in ulcerative colitis by fecal calprotectin vs. fecal immunochemical test. Am J Gastroenterol. 2015;110:873–880.
   PubMed Web of Science ®Google Scholar
• Calafat M, Cabré E, Mañosa M, et al. High within-day variability of fecal calprotectin levels in patients with active ulcerative colitis: what is the best timing for stool sampling? Inflammatory Bowel Dis. 2015;21:1072–1076.
   PubMed Web of Science ®Google Scholar
• Mosli MH, Zou G, Garg SK, et al. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110:802–819.
   PubMed Web of Science ®Google Scholar
• Ruemmele FM, Hyams JS, Otley A, et al. Outcome measures for clinical trials in pediatric IBD: an evidence-based, expert-driven practical statement paper of the pediatric ECCO committee. Gut. 2015;64:438–446.
   PubMed Web of Science ®Google Scholar
• Faubion WA, Fletcher JG, O'Byrne S, et al. Emerging biomarkers in inflammatory bowel disease (embark) study identifies fecal calprotectin, serum MMP9, and serum IL-22 as a novel combination of biomarkers for Crohn's disease activity: role of cross-sectional imaging. Am J Gastroenterol. 2013;108:1891–1900.
   PubMed Web of Science ®Google Scholar
• Turner D, Leach ST, Mack D, et al. Fecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: A prospective multicentre comparison of predicting outcomes and monitoring response. Gut. 2010;59:1207–1212.
   PubMed Web of Science ®Google Scholar
• Osterman MT, Aberra FN, Cross R, et al. Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. 2014;12:1887–1893.e3.
   PubMed Web of Science ®Google Scholar
• Molander P, Af Björkesten C, Mustonen H, et al. Fecal calprotectin concentration predicts outcome in inflammatory bowel disease after induction therapy with TNFa blocking agents. Inflamm Bowel Dis. 2012;18:2011–2017.
   PubMed Web of Science ®Google Scholar
• Molander P, Sipponen T, Kemppainen H, et al. Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD. J Crohns Colitis. 2013;7:730–735.
   PubMed Web of Science ®Google Scholar
• Reinisch W, Panés J, Khurana S, et al. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: Efficacy and safety from a phase IIa randomised multicentre study. Gut. 2015;64:894–900.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367:616–624.
   PubMed Web of Science ®Google Scholar
• Nash S, Stafford J, Madara JL. Effects of polymorphonuclear leukocyte transmigration on the barrier function of cultured intestinal epithelial monolayers. J Clin Invest. 1987;80:1104–1113.
   PubMed Web of Science ®Google Scholar
• Kucharzik T, Walsh SV, Chen J, et al. Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol. 2001;159:2001–2009.
   PubMed Web of Science ®Google Scholar
• Kucharzik T, Williams IR. Neutrophil migration across the intestinal epithelial barrier-summary of in vitro data and description of a new transgenic mouse model with doxycycline-inducible interleukin-8 expression in intestinal epithelial cells. Pathobiology 2002–2003;70:143–149.
   PubMed Web of Science ®Google Scholar
• Van Damme J, Van Beeumen J, Opdenakker G, et al. A novel, NH2-terminal sequence-characterized human monokine possessing neutrophil chemotactic, skin-reactive, and granulocytosis-promoting activity. J Exp Med. 1988;167:1364–1376.
   PubMed Web of Science ®Google Scholar
• Baggiolini M. Chemokines in pathology and medicine. J Intern Med. 2001;250:91–104.
   PubMed Web of Science ®Google Scholar
• Murdoch C, Finn A. Chemokine receptors and their role in inflammation and infectious diseases. Blood. 2000;95:3032–3043.
   PubMed Web of Science ®Google Scholar
• Mukaida N. Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol. 2003;284:L566–L577.
   PubMed Web of Science ®Google Scholar
• Traves SL, Smith SJ, Barnes PJ, et al. Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2. J Leukoc Biol. 2004;76:441–450.
   PubMed Web of Science ®Google Scholar
• Reutershan J, Morris MA, Burcin TL, et al. Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung. J Clin Invest. 2006;116:695–702.
   PubMed Web of Science ®Google Scholar
• Arijs I, De Hertogh G, Machiels K, et al. Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment. Am J Gastroenterol. 2011;106:748–761.
   PubMed Web of Science ®Google Scholar
• Stillie R, Farooq SM, Gordon JR, et al. The functional significance behind expressing two IL-8 receptor types on PMN. J Leukoc Biol. 2009;86:529–543.
   PubMed Web of Science ®Google Scholar
• Jones SA, Wolf M, Qin S, et al. Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2. Proc Natl Acad Sci U S A. 1996;93:6682–6686.
   PubMed Web of Science ®Google Scholar
• Kohler A, De Filippo K, Hasenberg M, et al. G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands. Blood. 2011;117:4349–4357.
   PubMed Web of Science ®Google Scholar
• Ranganathan P, Jayakumar C, Manicassamy S, et al. CXCR2 knockout mice are protected against DSS-colitis-induced acute kidney injury and inflammation. Am J Physiol Renal Physiol. 2013;305:F1422–F1427.
   PubMed Web of Science ®Google Scholar
• Chapman RW, Phillips JE, Hipkin RW, et al. CXCR2 antagonists for the treatment of pulmonary disease. Pharmacol Ther. 2009;121:55–68.
   PubMed Web of Science ®Google Scholar
• Nicholls DJ, Wiley K, Dainty I, et al. Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. J Pharmacol Exp Ther. 2015;353:340–350.
   PubMed Web of Science ®Google Scholar
• Jurcevic S, Humfrey C, Uddin M, et al. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions. Br J Clin Pharmacol. 2015;80:1324–1336.
   PubMed Web of Science ®Google Scholar
• Holz O, Khalilieh S, Ludwig-Sengpiel A, et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J. 2010;35:564–570.
   PubMed Web of Science ®Google Scholar
• Lazaar AL, Sweeney LE, MacDonald AJ, et al. SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br J Clin Pharmacol. 2011;72:282–293.
   PubMed Web of Science ®Google Scholar
• Virtala R, Ekman AK, Jansson L, et al. Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor. Clin Exp Allergy. 2012;42:590–596.
   PubMed Web of Science ®Google Scholar
• Moss RB, Mistry SJ, Konstan MW, et al. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros. 2013;12:241–248.
   PubMed Web of Science ®Google Scholar
• O'Sullivan S, Gilmer JF, Medina C. Matrix metalloproteinases in inflammatory bowel disease: an update. Mediators Inflamm. 2015;2015:964131.
   PubMed Web of Science ®Google Scholar
• Lakatos G, Hritz I, Varga MZ, et al. The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases. Dig Dis. 2012;30:289–295.
   PubMed Web of Science ®Google Scholar
• Matusiewicz M, Neubauer K, Mierzchala-Pasierb M, et al. Matrix metalloproteinase-9: its interplay with angiogenic factors in inflammatory bowel diseases. Dis Markers. 2014;2014:643645.
   PubMed Web of Science ®Google Scholar
• Annaházi A, Molnár T, Farkas K, et al. Fecal MMP-9: a new noninvasive differential diagnostic and activity marker in ulcerative colitis. Inflammatory Bowel Dis. 2013;19:316–320.
   PubMed Web of Science ®Google Scholar
• Hu J, Van den Steen PE, Sang QX, et al. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov. 2007;6:480–498.
   PubMed Web of Science ®Google Scholar
• Sandborn WJ, Bhandari BR, Fogel R, et al. Randomized clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis. Aliment Pharmacol Ther. 2016;44:157–169.
   PubMed Web of Science ®Google Scholar
• Yesil A, Gonen C, Senates E, et al. Relationship between neutrophil gelatinase-associated lipocalin (NGAL) levels and inflammatory bowel disease type and activity. Dig Dis Sci. 2013;58:2587–2593.
   PubMed Web of Science ®Google Scholar
• Stallhofer J, Friedrich M, Konrad-Zerna A, et al. Lipocalin-2 is a disease activity marker in inflammatory bowel disease regulated by IL-17A, IL-22, and TNF-alpha and modulated by IL23R genotype status. Inflamm Bowel Dis. 2015;21:2327–2340.
   PubMed Web of Science ®Google Scholar
• de Bruyn M, Arijs I, Wollants WJ, et al. Neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex as a surrogate serum marker of mucosal healing in ulcerative colitis. Inflamm Bowel Dis. 2014;20:1198–1207.
   PubMed Web of Science ®Google Scholar
• de Bruyn M, Arijs I, De Hertogh G, et al. Serum neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex as a surrogate marker for mucosal healing in patients with crohn's disease. J Crohns Colitis. 2015;9:1079–1087.
   PubMed Web of Science ®Google Scholar
• Schmid M, Fellermann K, Fritz P, et al. Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in crohn's disease. J Leukoc Biol. 2007;81:907–915.
   PubMed Web of Science ®Google Scholar
• Sinha S, Watorek W, Karr S, et al. Primary structure of human neutrophil elastase. Proc Natl Acad Sci U S A. 1987;84:2228–2232.
   PubMed Web of Science ®Google Scholar
• Rubin H. Serine protease inhibitors (SERPINS): where mechanism meets medicine. Nat Med. 1996;2:632–633.
   PubMed Web of Science ®Google Scholar
• Stone H, Pye A, Stockley RA. Disease associations in alpha-1-antitrypsin deficiency. Respir Med. 2014;108:338–343.
   PubMed Web of Science ®Google Scholar
• Adeyemi EO, Hodgson HJ. Faecal elastase reflects disease activity in active ulcerative colitis. Scand J Gastroenterol. 1992;27:139–142.
   PubMed Web of Science ®Google Scholar
• Adeyemi EO, Neumann S, Chadwick VS, et al. Circulating human leucocyte elastase in patients with inflammatory bowel disease. Gut. 1985;26:1306–1311.
   PubMed Web of Science ®Google Scholar
• Kuno Y, Ina K, Nishiwaki T, et al. Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitis. J Gastroenterol 2002;37:22–32.
   PubMed Web of Science ®Google Scholar
• Gouni-Berthold I, Baumeister B, Wegel E, et al. Neutrophil-elastase in chronic inflammatory bowel disease: a marker of disease activity? Hepatogastroenterology. 1999;46:2315–2320.
   PubMed Web of Science ®Google Scholar
• Henriksen PA. The potential of neutrophil elastase inhibitors as anti-inflammatory therapies. Curr Opin Hematol. 2014;21:23–28.
   PubMed Web of Science ®Google Scholar
• Vergnolle N. Protease inhibition as new therapeutic strategy for GI diseases. Gut. 2016;65:1215–1224.
   PubMed Web of Science ®Google Scholar
• Ruemmele FM, Targan SR, Levy G, et al. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology. 1998;115:822–829.
   PubMed Web of Science ®Google Scholar
• Zhou G, Song Y, Yang W, et al. ASCA, ANCA, ALCA and many more: are they useful in the diagnosis of inflammatory bowel disease? Dig Dis. 2016;34:90–97.
   PubMed Web of Science ®Google Scholar
• Dabek M, Ferrier L, Roka R, et al. Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. Am J Pathol. 2009;175:207–214.
   PubMed Web of Science ®Google Scholar
• Silberer H, Kuppers B, Mickisch O, et al. Fecal leukocyte proteins in inflammatory bowel disease and irritable bowel syndrome. Clin Lab. 2005;51:117–126.
   PubMed Web of Science ®Google Scholar
• Jucaite A, Svenningsson P, Rinne JO, et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in parkinson's disease. Brain. 2015;138:2687–2700.
   PubMed Web of Science ®Google Scholar
• Churg A, Marshall CV, Sin DD, et al. Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:34–43.
   PubMed Web of Science ®Google Scholar
• Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–194.
   PubMed Web of Science ®Google Scholar
• Matsuo K, Lin A, Procter JL, et al. Variations in the expression of granulocyte antigen NB1. Transfusion. 2000;40:654–662.
   PubMed Web of Science ®Google Scholar
• Beyrau M, Bodkin JV, Nourshargh S. Neutrophil heterogeneity in health and disease: a revitalized avenue in inflammation and immunity. Open Biol. 2012;2:120134.
   PubMed Web of Science ®Google Scholar
• Fossati G, Moots RJ, Bucknall RC, et al. Differential role of neutrophil fcgamma receptor IIIB (CD16) in phagocytosis, bacterial killing, and responses to immune complexes. Arthritis Rheum. 2002;46:1351–1361.
   PubMed Web of Science ®Google Scholar
• Molding DA, Hart CA, Edwards SW. Regulation of neutrophil FcgammaRIIIb (CD16) surface expression following delayed apoptosis in response to GM-CSF and sodium butyrate. J Leukoc Biol. 1999;65:875–882.
   PubMed Web of Science ®Google Scholar
• Dransfield I, Buckle AM, Savill JS, et al. Neutrophil apoptosis is associated with a reduction in CD16 (fc gamma RIII) expression. J Immunol. 1994;153:1254–1263.
   PubMed Web of Science ®Google Scholar
• Sebastian S, Ashton K, Houston Y, et al. Anti-TNF therapy induced immune neutropenia in crohns disease- report of 2 cases and review of literature. J Crohns Colitis. 2012;6:713–716.
   PubMed Web of Science ®Google Scholar
• Sachs UJ, Andrei-Selmer CL, Maniar A, et al. The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31). J Biol Chem. 2007;282:23603–23612.
   PubMed Web of Science ®Google Scholar
• Bayat B, Werth S, Sachs UJ, et al. Neutrophil transmigration mediated by the neutrophil-specific antigen CD177 is influenced by the endothelial S536N dimorphism of platelet endothelial cell adhesion molecule-1. J Immunol. 2010;184:3889–3896.
   PubMed Web of Science ®Google Scholar
• Kabakchiev B, Turner D, Hyams J, et al. Gene expression changes associated with resistance to intravenous corticosteroid therapy in children with severe ulcerative colitis. PLoS One. 2010;5:10–1371.
   Web of Science ®Google Scholar
• Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. J Transl Med. 2013;11:75. 5876-11-75.
   PubMed Web of Science ®Google Scholar
• Tillinger W, Jilch R, Jilma B, et al. Expression of the high-affinity IgG receptor FcRI (CD64) in patients with inflammatory bowel disease: a new biomarker for gastroenterologic diagnostics. Am J Gastroenterol. 2009;104:102–109.
   PubMed Web of Science ®Google Scholar
• Minar P, Haberman Y, Jurickova I, et al. Utility of neutrophil Fcγ receptor I (CD64) index as a biomarker for mucosal inflammation in pediatric Crohn's disease. Inflamm Bowel Dis. 2014;20:1037–1048.
   PubMed Web of Science ®Google Scholar
• Wojtal KA, Rogler G, Scharl M, et al. Fc gamma receptor CD64 modulates the inhibitory activity of infliximab. PLoS One. 2012;7:e43361.
   PubMed Web of Science ®Google Scholar
• Selsted ME, Ouellette AJ. Mammalian defensins in the antimicrobial immune response. Nat Immunol. 2005;6:551–557.
   PubMed Web of Science ®Google Scholar
• Ghosh D, Porter E, Shen B, et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol. 2002;3:583–590.
   PubMed Web of Science ®Google Scholar
• Cunliffe RN, Kamal M, Rose FR, et al. Expression of antimicrobial neutrophil defensins in epithelial cells of active inflammatory bowel disease mucosa. J Clin Pathol. 2002;55:298–304.
   PubMed Web of Science ®Google Scholar
• Schalkwijk J, Wiedow O, Hirose S. The trappin gene family: proteins defined by an N-terminal transglutaminase substrate domain and a C-terminal four-disulfide core. Biochem J. 1999;340:569–577.
   PubMed Web of Science ®Google Scholar
• Bergenfeldt M, Nyström M, Bohe M, et al. Localization of immunoreactive secretory leukocyte protease inhibitor (SLPI) in intestinal mucosa. J Gastroenterol. 1996;31:18–23.
   PubMed Web of Science ®Google Scholar
• Nuding S, Fellermann K, Wehkamp J, et al. Reduced mucosal antimicrobial activity in crohn's disease of the colon. Gut. 2007;56:1240–1247.
   PubMed Web of Science ®Google Scholar
• Savchenko AS, Inoue A, Ohashi R, et al. Long pentraxin 3 (PTX3) expression and release by neutrophils in vitro and in ulcerative colitis. Pathol Int. 2011;61:290–297.
   PubMed Web of Science ®Google Scholar
• Kato S, Ochiai M, Sakurada T, et al. Increased expression of long pentraxin PTX3 in inflammatory bowel diseases. Dig Dis Sci. 2008;53:1910–1916.
   PubMed Web of Science ®Google Scholar
• Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63:433–441.
   PubMed Web of Science ®Google Scholar
• Sands BE, Sandborn WJ, Feagan B, et al. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology. 2008;135:400–409.
   PubMed Web of Science ®Google Scholar