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01-10-2020 | Aprotinin | Original Research Paper

A role for mast cells and mast cell tryptase in driving neutrophil recruitment in LPS-induced lung inflammation via protease-activated receptor 2 in mice

Authors: Aline Dias de Almeida, Irismara Sousa Silva, Weslley Fernandes-Braga, Antônio Carlos Melo LimaFilho, R odrigo Machado Florentino, Ayslan Barra, Luciana de Oliveira Andrade, M. Fátima Leite, Geovanni Dantas Cassali, André Klein

Published in: Inflammation Research | Issue 10/2020

Abstract

Objective

This study aims to investigate the role of protease-activated receptor (PAR) 2 and mast cell (MC) tryptase in LPS-induced lung inflammation and neutrophil recruitment in the lungs of C57BL/6 mice.

Methods

C57BL/6 mice were pretreated with the PAR2 antagonist ENMD-1068, compound 48/80 or aprotinin prior to intranasal instillation of MC tryptase or LPS. Blood leukocytes, C-X-C motif chemokine ligand (CXCL) 1 production leukocytes recovered from bronchoalveolar lavage fluid (BALF), and histopathological analysis of the lung were evaluated 4 h later. Furthermore, we performed experiments to determine intracellular calcium signaling in RAW 264.7 cells stimulated with LPS in the presence or absence of a protease inhibitor cocktail or ENMD-1068 and evaluated PAR2 expression in the lungs of LPS-treated mice.

Results

Pharmacological blockade of PAR2 or inhibition of proteases reduced neutrophils recovered in BALF and LPS-induced calcium signaling. PAR2 blockade impaired LPS-induced lung inflammation, PAR2 expression in the lung and CXCL1 release in BALF, and increased circulating blood neutrophils. Intranasal instillation of MC tryptase increased the number of neutrophils recovered in BALF, and MC depletion with compound 48/80 impaired LPS-induced neutrophil migration.

Conclusion

Our study provides, for the first time, evidence of a pivotal role for MCs and MC tryptase in neutrophil migration, lung inflammation and macrophage activation triggered by LPS, by a mechanism dependent on PAR2 activation.

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Aghasafari P, George U, Pidaparti R. A review of inflammatory mechanism in airway diseases. Inflamm Res. 2019;68:59–74.PubMed

Petri B, Sanz MJ. Neutrophil chemotaxis. Cell Tissue Res. 2018;371:425–36.PubMed

Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012;30:459–89.PubMed

Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989;320:365–76.PubMed

Hollenberg MD, Compton SJ. International union of pharmacology. XXVIII proteinase-activated receptors. Pharmacol. Rev. 2002;54:203–17.PubMed

Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991;64:1057–68.PubMed

Rallabhandi P, Nhu QM, Toshchakov VY, Piao W, Medvedev AE, Hollenberg MD, et al. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem. 2008;283:24314–25.PubMedPubMedCentral

Cicala C. Protease activated receptor 2 and the cardiovascular system. Br J Pharmacol. 2002;135:14–20.PubMedPubMedCentral

Kawabata A, Kuroda R, Minami T, Kataoka K, Taneda M. Increased vascular permeability by a specific agonist of protease-activated receptor-2 in rat hindpaw. Br J Pharmacol. 1998;125:419–22.PubMedPubMedCentral

10.

Vergnolle N. Review article: proteinase-activated receptors—novel signals for gastrointestinal pathophysiology. Aliment PharmacolTher. 2000;14:257–66.

11.

Cocks TM, Moffatt JD. Protease-activated receptor-2 (PAR2) in the airways. Pulm Pharmacol Ther. 2001;14:183–91.PubMed

12.

Agier J, Pastwińska J, Brzezińska-Błaszczyk E. An overview of mast cell pattern recognition receptors. Inflamm Res. 2018;67:737–46.PubMedPubMedCentral

13.

González-de-Olano D, Álvarez-Twose I. Mast cells as key players in allergy and inflammation. J Investig Allergol Clin Immunol. 2018;28:365–78.PubMed

14.

Agier J, Żelechowska P, Kozłowska E, Brzezińska-Błaszczyk E. Expression of surface and intracellular Toll-like receptors by mature mast cells. Cent Eur J Immunol. 2016;41:333–8.PubMed

15.

Di Nardo A, Vitiello A, Gallo RL. Mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol. 2003;170:2274–8.PubMed

16.

Di Nardo A, Yamasaki K, Dorschner RA, Lai Y, Gallo RL. Mast cell cathelicidin antimicrobial peptide prevents invasive group A Streptococcus infection of the skin. J Immunol. 2008;180:7565–73.PubMedPubMedCentral

17.

Shpacovitch VM, Seeliger S, Huber-Lang M, Balkow S, Feld M, Hollenberg MD, et al. Agonists of proteinase-activated receptor-2 affect transendothelial migration and apoptosis of human neutrophils. Exp Dermatol. 2007;16:799–806.PubMed

18.

Rothmeier AS, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol. 2012;34:133–49.PubMed

19.

Van den Boogaard FE, Brands X, Duitman J, de Stoppelaar SF, Borensztajn KS, Roelofs JJTH, et al. Protease-activated receptor 2 facilitates bacterial dissemination in pneumococcal pneumonia. J Infect Dis. 2018;217:1462–71.PubMed

20.

Howells GL, Macey MG, Chinni C, Hou L, Fox MT, Harriott P, et al. Proteinase-activated receptor-2: expression by human neutrophils. J Cell Sci. 1997;110:881–7.PubMed

21.

Roche N, Stirling RG, Lim S, Oliver BG, Oates T, Jazrawi E, et al. Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages. J Allergy Clin Immunol. 2003;111:367–73.PubMed

22.

Shpacovitch VM, Feld M, Holzinger D, Kido M, Hollenberg MD, Levi-Schaffer F, et al. Role of proteinase-activated receptor-2 in anti-bacterial and immunomodulatory effects of interferon-γ on human neutrophils and monocytes. Immunology. 2011;133:329–39.PubMedPubMedCentral

23.

Klein A, Talvani A, Silva PM, Martins MA, Wells TN, Proudfoot A, et al. Stem cell factor-induced leukotriene B4 production cooperates with eotaxin to mediate the recruitment of eosinophils during allergic pleurisy in mice. J Immunol. 2001;167:524–31.PubMed

24.

Horvat JC, Beagley KW, Wade MA, Preston JA, Hansbro NG, Hickey DK, et al. Neonatal chlamydial infection induces mixed T-cell responses that drive allergic airway disease. Am J Respir Crit Care Med. 2007;176:556–64.PubMed

25.

Garcia CC, Russo RC, Guabiraba R, Fagundes CT, Polidoro RB, Tavares LP, et al. Platelet-activating factor receptor plays a role in lung injury and death caused by influenza A in mice. PLoS Pathog. 2010;6:e1001171.PubMedPubMedCentral

26.

Parasuraman S, Raveendran R, Kesavan R. Blood sample collection in small laboratory animals. J Pharmacol Pharmacother. 2010;1:87–93.PubMedPubMedCentral

27.

Su YC, Wu WM, Wu MF, Chiang BL. A model of chronic lymphocytic leukemia with Ritcher’s transformation in severe combined immunodeficiency mice. Exp Hematol. 2001;29:1218–25.PubMed

28.

Schlosser SF, Burgstahler AD, Nathanson MH. Isolated rat hepatocytes can signal to other hepatocytes and bile duct cells by release of nucleotides. Proc Natl Acad Sci USA. 1996;93:9948–53.PubMed

29.

Leite MF, Thrower EC, Echevarria W, Koulen P, Hirata K, Bennett AM, et al. Nuclear and cytosolic calcium are regulated independently. Proc Natl Acad Sci USA. 2003;100:2975–80.PubMed

30.

Di Rosa M, Giroud JP, Willoughby DA. Studies on the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J Pathol. 1971;104:15–29.PubMed

31.

Ramos CD, Heluy-Neto NE, Ribeiro RA, Ferreira SH, Cunha FQ. Neutrophil migration induced by IL-8-activated mast cells is mediated by CINC-1. Cytokine. 2003;21:214–23.PubMed

32.

Schmidlin F, Amadesi S, Dabbagh K, Lewis DE, Knott P, Bunnett NW, et al. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol. 2002;169:5315–21.PubMed

33.

Davidson CE, Asaduzzaman M, Arizmendi NG, Polley D, Wu Y, Gordon JR, et al. Proteinase-activated receptor-2 activation participates in allergic sensitization to house dust mite allergens in a murine model. Clin Exp Allergy. 2013;43:1274–85.PubMed

34.

de Boer JD, Van'tVeer C, Stroo I, van der Meer AJ, de Vos AF, van der Zee JS, et al. Protease-activated receptor-2 deficient mice have reduced house dust mite-evoked allergic lung inflammation. Innate Immun. 2014;20:618–25.PubMed

35.

Asaduzzaman M, Nadeem A, Arizmendi N, Davidson C, Nichols HL, Abel M, et al. Functional inhibition of PAR2 alleviates allergen-induced airway hyperresponsiveness and inflammation. Clin Exp Allergy. 2015;45:1844–55.PubMed

36.

Williams JC, Lee RD, Doerschuk CM, Mackman N. Effect of PAR-2 deficiency in mice on KC expression after intratracheal LPS administration. J Signal Transduct. 2011;2011:415195.PubMedPubMedCentral

37.

Pejler G, Ronnberg E, Waern I, Wernersson S. Mast cell proteases: multifaceted regulators of inflammatory disease. Blood. 2010;115:4981–90.PubMed

38.

Compton SJ, Cairns JA, Holgate ST, Walls AF. The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells. J Immunol. 1998;161:1939–46.PubMed

39.

He S, Peng Q, Walls AF. Potent induction of a neutrophil and eosinophil-rich infiltrate in vivo by human mast cell tryptase: selective enhancement of eosinophil recruitment by histamine. J Immunol. 1997;159:6216–25.PubMed

40.

Schmidlin F, Amadesi S, Vidil R, Trevisani M, Martinet N, Caughey G, et al. Expression and function of proteinase-activated receptor 2 in human bronchial smooth muscle. Am J Respir Crit Care Med. 2001;164:1276–81.PubMed

41.

Huang C, Friend DS, Qiu WT, Wong GW, Morales G, Hunt J, et al. Induction of a selective and persistent extravasation of neutrophils into the peritoneal cavity by tryptase mouse mast cell protease 6. J Immunol. 1998;160:1910–9.PubMed

42.

Thakurdas SM, Melicoff E, Sansores-Garcia L, Moreira DC, Petrova Y, Stevens RL, et al. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J Biol Chem. 2007;282:20809–155.PubMed

43.

Reynolds DS, Gurley DS, Austen KF, Serafine WE. Cloning of the cDNA and gene of mouse mast cell protease-6-transcription by progenitor mast cells and mast cells of the connective tissue subclass. J Biol Chem. 1991;266(6):3847–53.PubMed

44.

Caughey GH. Protease mediators of anaphylaxis, chapter 6. In: Castells MC, editor. Anaphylaxis and hypersensitivity reactions. p. 89–106; 2011. ISBN 978-1-60327-950-5. https://doi.org/10.1007/978-1-60327-951-2

45.

Matos NA, Silva JF, Matsui TC, Damasceno KA, Duarte ID, Lemos VS, et al. Mast cell tryptase induces eosinophil recruitment in the pleural cavity of mice via proteinase-activated receptor 2. Inflammation. 2013;36:1260–7.PubMed

46.

Lohman RJ, Cotterell AJ, Barry GD, Liu L, Suen JY, Vesey DA, et al. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J. 2012;26:2877–87.PubMed

47.

Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, et al. A short-term model of COPD identifies a role for mast cell tryptase. J Allergy Clin Immunol. 2013;131(3):752–62.PubMedPubMedCentral

48.

Reed DE, Barajas-Lopez C, Cottrell G, Velazquez-Rocha S, Dery O, Grady EF, et al. Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons. J Physiol. 2003;547(2):531–42.PubMedPubMedCentral

49.

Oshiro A, Otani H, Yagi Y, Fukuhara S, Inagaki C. Protease-activated receptor-2-mediated inhibition for Ca²⁺ response to lipopolysaccharide in Guinea pig tracheal epithelial cells. Am J Respir Cell Mol Biol. 2004;30:886–92.PubMed

50.

Krishna MT, Chauhan A, Little L, Sampson K, Hawksworth R, Mant T, et al. Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma. J Allergy Clin Immunol. 2001;107:1039–45.PubMed

51.

Matos NA, Silva JF, Damasceno KA, Cassali GD, Lemos VS, Duarte ID, et al. Proteinase-activated receptor 2 blockade impairs CCL11- or allergen-induced eosinophil recruitment in experimental pleurisy. Eur J Pharmacol. 2014;740:627–33.PubMed

52.

Miike S, McWilliam AS, Kita H. Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2. J Immunol. 2001;167:6615–22.PubMed

53.

Senden NH, Jeunhomme TM, Heemskerk JW, Wagenvoord R, van’t Veer C, Hemker HC, et al. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol. 1998;161:4318–24.PubMed

54.

Ostrowska E, Sokolova E, Reiser G. PAR-2 activation and LPS synergistically enhance inflammatory signaling in airway epithelial cells by raising PAR expression level and interleukin-8 release. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1208–L12181218.PubMed

55.

Chao HH, Chen PY, Hao WR, Chiang WP, Cheng TH, Loh SH, et al. Lipopolysaccharide pretreatment increases protease-activated receptor-2 expression and monocyte chemoattractant protein-1 secretion in vascular endothelial cells. J Biomed Sci. 2017;24:85.PubMedPubMedCentral

56.

Bakele M, Lotz-Havla AS, Jakowetz A, Carevic M, Marcos V, Muntau AC, et al. An interactive network of elastase, secretases, and PAR-2 protein regulates CXCR1 receptor surface expression on neutrophils. J Biol Chem. 2014;289:20516–25.PubMedPubMedCentral

57.

Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004;4:787–99.PubMed

Title: A role for mast cells and mast cell tryptase in driving neutrophil recruitment in LPS-induced lung inflammation via protease-activated receptor 2 in mice
Authors: Aline Dias de Almeida
Irismara Sousa Silva
Weslley Fernandes-Braga
Antônio Carlos Melo LimaFilho
R odrigo Machado Florentino
Ayslan Barra
Luciana de Oliveira Andrade
M. Fátima Leite
Geovanni Dantas Cassali
André Klein
Publication date: 01-10-2020
Publisher: Springer International Publishing
Keyword: Aprotinin
Published in: Inflammation Research / Issue 10/2020
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-020-01376-4

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Results

Conclusion

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