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05.03.2021 | Original Article

Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases

verfasst von: Bert Malengier-Devlies, Mieke Metzemaekers, Mieke Gouwy, Erika Van Nieuwenhove, Albrecht Betrains, Maaike Cockx, Lotte Vanbrabant, Noëmie Pörtner, Jurgen Vercauteren, Lien De Somer, Sofie Struyf, Steven Vanderschueren, Ellen De Langhe, Paul Proost, Patrick Matthys, Carine Wouters

Erschienen in: Journal of Clinical Immunology | Ausgabe 5/2021

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Abstract

Purpose

Familial Mediterranean Fever (FMF) and Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) are clinically distinct autoinflammatory disorders caused by mutations in the pyrin-encoding gene MEFV. We investigated the transcriptional, phenotypical, and functional characteristics of patient neutrophils to explore their potential role in FMF and PAAND pathophysiology.

Methods

RNA sequencing was performed to discover transcriptional aberrancies. The phenotypical features, degranulation properties, and phagocytic capacity of neutrophils were assessed by flow cytometry. Production of reactive oxygen species (ROS), myeloperoxidase (MPO) release, and chemotactic responses were investigated via chemiluminescence, ELISA, and Boyden chamber assays, respectively.

Results

Neutrophils from PAAND and FMF patients showed a partially overlapping, activated gene expression profile with increased expression of S100A8, S100A9, S100A12, IL-4R, CD48, F5, MMP9, and NFKB. Increased MMP9 and S100A8/A9 expression levels were accompanied by high plasma concentrations of the encoded proteins. Phenotypical analysis revealed that neutrophils from FMF patients exhibited an immature character with downregulation of chemoattractant receptors CXCR2, C5aR, and BLTR1 and increased expression of Toll-like receptor 4 (TLR4) and TLR9. PAAND neutrophils displayed an increased random, but reduced CXCL8-induced migration. A tendency for enhanced random migration was observed for FMF neutrophils. PAAND neutrophils showed a moderately but significantly enhanced phagocytic activity as opposed to neutrophils from FMF patients. Neutrophils from both patient groups showed increased MPO release and ROS production.

Conclusions

Neutrophils from patients with FMF and PAAND, carrying different mutations in the MEFV gene, share a pro-inflammatory phenotype yet demonstrate diverse features, underscoring the distinction between both diseases.

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Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.PubMedPubMedCentralCrossRef

de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823–74.PubMedPubMedCentralCrossRef

Harapas CR, Steiner A, Davidson S, Masters SL. An update on autoinflammatory diseases: inflammasomopathies. Curr Rheumatol Rep. 2018;20:40.PubMedCrossRef

Mathur A, Hayward JA, Man SM. Molecular mechanisms of inflammasome signaling. J Leukoc Biol. 2018;103:233–57.PubMed

Hayward JA, Mathur A, Ngo C, Man SM. Cytosolic recognition of microbes and pathogens: inflammasomes in action. Microbiol Mol Biol Rev. 2018;82.

Liston A, Masters SL. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol. 2017;17:208–14.PubMedCrossRef

Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyt development and is regulated in response to inflammatory mediators. Blood. 2000;95:3223–31.PubMedCrossRef

Heilig R, Broz P. Function and mechanism of the pyrin inflammasome. Eur J Immunol. 2018;48:230–8.PubMedCrossRef

de Torre-Minguela C, Mesa Del Castillo P, Pelegrin P. The NLRP3 and pyrin inflammasomes: implications in the pathophysiology of autoinflammatory diseases. Front Immunol. 2017;8:43.PubMedPubMedCentral

10.

Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016;17:914–21.PubMedPubMedCentralCrossRef

11.

Aubert DF, Xu H, Yang J, Shi X, Gao W, Li L, et al. A burkholderia type VI effector deamidates Rho GTPases to activate the pyrin inflammasome and trigger inflammation. Cell Host Microbe. 2016;19:664–74.PubMedCrossRef

12.

Xu H, Yang J, Gao W, Li L, Li P, Zhang L, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature. 2014;513:237–41.PubMedCrossRef

13.

Gavrilin MA, Abdelaziz DHA, Mostafa M, Abdulrahman BA, Grandhi J, Akhter A, et al. Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia. J Immunol. 2012;188:3469–77.PubMedCrossRef

14.

Dumas A, Amiable N, de Rivero Vaccari JP, Chae JJ, Keane RW, Lacroix S, et al. The inflammasome pyrin contributes to pertussis toxin-induced IL-1beta synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis. PLoS Pathog. 2014;10:e1004150.PubMedPubMedCentralCrossRef

15.

Manukyan G, Aminov R. Update on Pyrin functions and mechanisms of familial mediterranean fever. Front Microbiol. 2016;7:456.PubMedPubMedCentralCrossRef

16.

Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G, Woo P, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74:799–805.PubMedCrossRef

17.

Moghaddas F, Llamas R, De Nardo D, Martinez-Banaclocha H, Martinez-Garcia JJ, Mesa-Del-Castillo P, et al. A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to familial mediterranean fever. Ann Rheum Dis. 2017;76:2085–94.PubMedCrossRef

18.

Masters SL, Lagou V, Jeru I, Baker PJ, Van Eyck L, Parry DA, et al. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci Transl Med. 2016;8:332ra45.PubMedCrossRef

19.

Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75:644–51.PubMedCrossRef

20.

Liew PX, Kubes P. The neutrophil’s role during health and disease. Physiol Rev. 2019;99:1223–48.PubMedCrossRef

21.

Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol. 2014;15:602–11.PubMedCrossRef

22.

Manukyan G, Petrek M, Kriegova E, Ghazaryan K, Fillerova R, Boyajyan A. Activated phenotype of circulating neutrophils in familial Mediterranean fever. Immunobiology. 2013;218:892–8.PubMedCrossRef

23.

Mitroulis I, Kourtzelis I, Kambas K, Chrysanthopoulou A, Ritis K. Evidence for the involvement of mTOR inhibition and basal autophagy in familial Mediterranean fever phenotype. Hum Immunol. 2011;72:135–8.PubMedCrossRef

24.

Apostolidou E, Skendros P, Kambas K, Mitroulis I, Konstantinidis T, Chrysanthopoulou A, et al. Neutrophil extracellular traps regulate IL-1beta-mediated inflammation in familial Mediterranean fever. Ann Rheum Dis. 2016;75:269–77.PubMedCrossRef

25.

Stoler I, Freytag J, Orak B, Unterwalder N, Henning S, Heim K, et al. Gene-dose effect of MEFV gain-of-function mutations determines ex vivo neutrophil activation in familial mediterranean fever. Front Immunol. 2020;11:716.PubMedPubMedCentralCrossRef

26.

Vandooren J, Geurts N, Martens E, Van den Steen PE, Opdenakker G. Zymography methods for visualizing hydrolytic enzymes. Nat Methods. 2013;10:211–20.PubMedCrossRef

27.

Metzemaekers M, Vandendriessche S, Berghmans N, Gouwy M, Proost P. Truncation of CXCL8 to CXCL8(9-77) enhances actin polymerization and in vivo migration of neutrophils. J Leukoc Biol. 2020;107:1167–73.PubMedCrossRef

28.

De Buck M, Berghmans N, Portner N, Vanbrabant L, Cockx M, Struyf S, et al. Serum amyloid A1alpha induces paracrine IL-8/CXCL8 via TLR2 and directly synergizes with this chemokine via CXCR2 and formyl peptide receptor 2 to recruit neutrophils. J Leukoc Biol. 2015;98:1049–60.PubMedCrossRef

29.

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.PubMedPubMedCentralCrossRef

30.

Marini O, Costa S, Bevilacqua D, Calzetti F, Tamassia N, Spina C, et al. Mature CD10 ⁺ and immature CD10 ⁻ neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood. 2017;129:3271.CrossRef

31.

Sengelov H, Follin P, Kjeldsen L, Lollike K, Dahlgren C, Borregaard N. Mobilization of granules and secretory vesicles during in vivo exudation of human neutrophils. J Immunol. 1995;154:4157–65.PubMedCrossRef

32.

Guma M, Ronacher L, Liu-Bryan R, Takai S, Karin M, Corr M. Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation. Arthritis Rheum. 2009;60:3642–50.PubMedPubMedCentralCrossRef

33.

Mankan AK, Dau T, Jenne D, Hornung V. The NLRP3/ASC/Caspase-1 axis regulates IL-1beta processing in neutrophils. Eur J Immunol. 2012;42:710–5.PubMedCrossRef

34.

Karmakar M, Sun Y, Hise AG, Rietsch A, Pearlman E. Cutting edge: IL-1beta processing during Pseudomonas aeruginosa infection is mediated by neutrophil serine proteases and is independent of NLRC4 and caspase-1. J Immunol. 2012;189:4231–5.PubMedCrossRef

35.

Chen KW, Gross CJ, Sotomayor FV, Stacey KJ, Tschopp J, Sweet MJ, et al. The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge. Cell Rep. 2014;8:570–82.PubMedCrossRef

36.

Karmakar M, Katsnelson M, Malak HA, Greene NG, Howell SJ, Hise AG, et al. Neutrophil IL-1beta processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux. J Immunol. 2015;194:1763–75.PubMedCrossRef

37.

Perez-Figueroa E, Torres J, Sanchez-Zauco N, Contreras-Ramos A, Alvarez-Arellano L, Maldonado-Bernal C. Activation of NLRP3 inflammasome in human neutrophils by Helicobacter pylori infection. Innate Immun. 2016;22:103–12.PubMedCrossRef

38.

Mohammadi N, Midiri A, Mancuso G, Patane F, Venza M, Venza I, et al. Neutrophils directly recognize group B streptococci and contribute to interleukin-1beta production during infection. PLoS One. 2016;11:e0160249.PubMedPubMedCentralCrossRef

39.

Balci-Peynircioglu B, Akkaya-Ulum YZ, Avci E, Batu ED, Purali N, Ozen S, et al. Potential role of pyrin, the protein mutated in familial Mediterranean fever, during inflammatory cell migration. Clin Exp Rheumatol. 2018;36:116–24.PubMed

40.

Ramos MV, Ruggieri M, Panek AC, Mejias MP, Fernandez-Brando RJ, Abrey-Recalde MJ, et al. Association of haemolytic uraemic syndrome with dysregulation of chemokine receptor expression in circulating monocytes. Clin Sci. 2015;129:235–44.CrossRef

41.

Ravi AK, Plumb J, Gaskell R, Mason S, Broome CS, Booth G, et al. COPD monocytes demonstrate impaired migratory ability. Respir Res. 2017;18:90.PubMedPubMedCentralCrossRef

42.

D’Amico G, Frascaroli G, Bianchi G, Transidico P, Doni A, Vecchi A, et al. Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys. Nat Immunol. 2000;1:387–91.PubMedCrossRef

43.

Metzemaekers M, Gouwy M, Proost P. Neutrophil chemoattractant receptors in health and disease: double-edged swords. Cell Mol Immunol. 2020;17:433–50.PubMedPubMedCentralCrossRef

44.

Lidar M, Scherrmann J-M, Shinar Y, Chetrit A, Niel E, Gershoni-Baruch R, et al. Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization. Semin Arthritis Rheum. 2004;33:273–82.PubMedCrossRef

45.

Bonfoco E, Ceccatelli S, Manzo L, Nicotera P. Colchicine induces apoptosis in cerebellar granule cells. Exp Cell Res. 1995;218:189–200.PubMedCrossRef

46.

Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther. 2014;36:1465–79.PubMedCrossRef

47.

Coelho FM, Pinho V, Amaral FA, Sachs D, Costa VV, Rodrigues DH, et al. The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature. Arthritis Rheum. 2008;58:2329–37.PubMedCrossRef

48.

Angelidis C, Kotsialou Z, Kossyvakis C, Vrettou A-R, Zacharoulis A, Kolokathis F, et al. Colchicine pharmacokinetics and mechanism of action. Curr Pharm Des. 2018;24:659–63.PubMedCrossRef

Titel: Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases
verfasst von: Bert Malengier-Devlies
Mieke Metzemaekers
Mieke Gouwy
Erika Van Nieuwenhove
Albrecht Betrains
Maaike Cockx
Lotte Vanbrabant
Noëmie Pörtner
Jurgen Vercauteren
Lien De Somer
Sofie Struyf
Steven Vanderschueren
Ellen De Langhe
Paul Proost
Patrick Matthys
Carine Wouters
Publikationsdatum: 05.03.2021
Verlag: Springer US
Erschienen in: Journal of Clinical Immunology / Ausgabe 5/2021
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-021-01008-4

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Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

Purpose

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