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Respiratory Research
Published in: Respiratory Research 1/2020

Open Access 01-12-2020 | Bronchial Asthma | Research

T2 and T17 cytokines alter the cargo and function of airway epithelium-derived extracellular vesicles

Authors: Elisabeth Ax, Zala Jevnikar, Aleksander Cvjetkovic, Carina Malmhäll, Henric Olsson, Madeleine Rådinger, Cecilia Lässer

Published in: Respiratory Research | Issue 1/2020

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Abstract

Background

Asthma is a common and heterogeneous disease that includes subgroups characterized by type 2 (T2) or type 17 (T17) immune responses for which there is a need to identify the underlying mechanisms and biomarkers in order to develop specific therapies. These subgroups can be defined by airway epithelium gene signatures and the airway epithelium has also been implicated to play a significant role in asthma pathology. Extracellular vesicles (EVs) carry functional biomolecules and participate in cell-to-cell communication in both health and disease, properties that are likely to be involved in airway diseases such as asthma. The aim of this study was to identify stimulus-specific proteins and functionality of bronchial epithelium-derived EVs following stimulation with T2 or T17 cytokines.

Methods

EVs from cytokine-stimulated (T2: IL-4 + IL-13 or T17: IL-17A + TNFα) human bronchial epithelial cells cultured at air-liquid interface (HBEC-ALI) were isolated by density cushion centrifugation and size exclusion chromatography and characterized with Western blotting and electron microscopy. Transcriptomic (cells) and proteomic (EVs) profiling was also performed.

Results

Our data shows that EVs are secreted and can be isolated from the apical side of HBEC-ALI and that cytokine stimulation increases EV release. Genes upregulated in cells stimulated with T2 or T17 cytokines were increased also on protein level in the EVs. Proteins found in T17-derived EVs were suggested to be involved in pathways related to neutrophil movement which was supported by assessing neutrophil chemotaxis ex vivo.

Conclusions

Together, the results suggest that epithelial EVs are involved in airway inflammation and that the EV proteome may be used for discovery of disease-specific mechanisms and signatures which may enable a precision medicine approach to the treatment of asthma.
Appendix
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Literature
1.
Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5:691–706.
2.
3.
Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391:783–800.PubMed
4.
Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;11:577–84.PubMedPubMedCentral
5.
McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008;181:4089–97.PubMed
6.
Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11:54–61.PubMed
7.
Hart KM, Choy DF, Bradding P, Wynn TA, Arron JR. Accurately measuring and modeling Th2 and Th17 endotypes in severe asthma. Ann Transl Med. 2017;5:91.PubMedPubMedCentral
8.
Weitnauer M, Mijosek V, Dalpke AH. Control of local immunity by airway epithelial cells. Mucosal Immunol. 2016;9:287–98.PubMed
9.
Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A. 2007;104:15858–63.PubMedPubMedCentral
10.
Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015;7:301ra129.PubMed
11.
Jevnikar Z, Ostling J, Ax E, Calven J, Thorn K, Israelsson E, Oberg L, Singhania A, Lau LCK, Wilson SJ, et al. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. J Allergy Clin Immunol. 2019;143(2):577–90. https://​doi.​org/​10.​1016/​j.​jaci.​2018.​05.​026. Epub 2018 Jun 11.
12.
Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, Hoda U, Rossios C, Sousa A, Wilson SJ, et al. A Transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED. Am J Respir Crit Care Med. 2017;195:443–55.PubMed
13.
El-Andaloussi S, Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12:347–57.PubMed
14.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMed
15.
Kesimer M, Scull M, Brighton B, DeMaria G, Burns K, O'Neal W, Pickles RJ, Sheehan JK. Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J. 2009;23:1858–68.PubMedPubMedCentral
16.
Barile L, Vassalli G. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63–78.PubMed
17.
Xu R, Greening DW, Zhu HJ, Takahashi N, Simpson RJ. Extracellular vesicle isolation and characterization: toward clinical application. J Clin Invest. 2016;126:1152–62.PubMedPubMedCentral
18.
Torregrosa Paredes P, Esser J, Admyre C, Nord M, Rahman QK, Lukic A, Radmark O, Gronneberg R, Grunewald J, Eklund A, et al. Bronchoalveolar lavage fluid exosomes contribute to cytokine and leukotriene production in allergic asthma. Allergy. 2012;67:911–9.PubMed
19.
Hough KP, Trevor JL, Strenkowski JG, Wang Y, Chacko BK, Tousif S, Chanda D, Steele C, Antony VB, Dokland T, et al. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol. 2018;18:54–64.PubMedPubMedCentral
20.
Kulshreshtha A, Ahmad T, Agrawal A, Ghosh B. Proinflammatory role of epithelial cell-derived exosomes in allergic airway inflammation. J Allergy Clin Immunol. 2013;131(1194–1203):1203.e1191–14.
21.
Sanchez-Vidaurre S, Eldh M, Larssen P, Daham K, Martinez-Bravo MJ, Dahlen SE, Dahlen B, van Hage M, Gabrielsson S. RNA-containing exosomes in induced sputum of asthmatic patients. J Allergy Clin Immunol. 2017;140:1459–1461.e1452.PubMed
22.
Lasser C, O'Neil SE, Shelke GV, Sihlbom C, Hansson SF, Gho YS, Lundback B, Lotvall J. Exosomes in the nose induce immune cell trafficking and harbour an altered protein cargo in chronic airway inflammation. J Transl Med. 2016;14:181.PubMedPubMedCentral
23.
Karimi N, Cvjetkovic A, Jang SC, Crescitelli R, Hosseinpour Feizi MA, Nieuwland R, Lotvall J, Lasser C. Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins. Cell Mol Life Sci. 2018;75:2873–86.PubMedPubMedCentral
24.
Wisniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods. 2009;6:359–62.PubMed
25.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.PubMedPubMedCentral
26.
Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O, Charbord P, Domenech J. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007;25:1737–45.PubMed
27.
Kim DK, Kang B, Kim OY, Choi DS, Lee J, Kim SR, Go G, Yoon YJ, Kim JH, Jang SC, et al. EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles. J Extracell Vesicles. 2013;2.
28.
Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, Bond VC, Borras FE, Breakefield X, Budnik V, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012;10:e1001450.PubMedPubMedCentral
29.
Abels ER, Breakefield XO. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell Mol Neurobiol. 2016;36:301–12.PubMedPubMedCentral
30.
Leidal AM, Debnath J. Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles. Methods. 2020.
31.
32.
van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.PubMed
33.
Henne WM, Buchkovich NJ, Emr SD. The ESCRT pathway. Dev Cell. 2011;21:77–91.PubMed
34.
Boyle EI, Weng S, Gollub J, Jin H, Botstein D, Cherry JM, Sherlock G. GO::TermFinder--open source software for accessing gene ontology information and finding significantly enriched gene ontology terms associated with a list of genes. Bioinformatics. 2004;20:3710–5.PubMed
35.
Larose MC, Chakir J, Archambault AS, Joubert P, Provost V, Laviolette M, Flamand N. Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: involvement in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2015;136:904–13.PubMed
36.
Silkoff PE, Laviolette M, Singh D, FitzGerald JM, Kelsen S, Backer V, Porsbjerg CM, Girodet PO, Berger P, Kline JN, et al. Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. J Allergy Clin Immunol. 2017;140:710–9.PubMed
37.
Chu HW, Balzar S, Westcott JY, Trudeau JB, Sun Y, Conrad DJ, Wenzel SE. Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition. Clin Exp Allergy. 2002;32:1558–65.PubMed
38.
Nozato K, Fujita J, Kawaguchi M, Ohara G, Morishima Y, Ishii Y, Huang SK, Kokubu F, Satoh H, Hizawa N. IL-17F induces CCL20 in bronchial epithelial cells. J Allergy (Cairo). 2011;2011:587204.
39.
Franke A, Balschun T, Sina C, Ellinghaus D, Hasler R, Mayr G, Albrecht M, Wittig M, Buchert E, Nikolaus S, et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet. 2010;42:292–4.PubMed
40.
Nakao I, Kanaji S, Ohta S, Matsushita H, Arima K, Yuyama N, Yamaya M, Nakayama K, Kubo H, Watanabe M, et al. Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease. J Immunol. 2008;180:6262–9.PubMed
41.
Park JA, Sharif AS, Tschumperlin DJ, Lau L, Limbrey R, Howarth P, Drazen JM. Tissue factor-bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo. J Allergy Clin Immunol. 2012;130:1375–83.PubMedPubMedCentral
42.
Bartel S, La Grutta S, Cilluffo G, Perconti G, Bongiovanni A, Giallongo A, Behrends J, Kruppa J, Hermann S, Chiang D, et al. Human airway epithelial extracellular vesicle miRNA signature is altered upon asthma development. Allergy. 2020;75(2):346–56. https://​doi.​org/​10.​1111/​all.​14008. Epub 2019 Oct 2.
43.
Gupta R, Radicioni G, Abdelwahab S, Dang H, Carpenter J, Chua M, Mieczkowski PA, Sheridan JT, Randell SH, Kesimer M. Intercellular communication between airway epithelial cells is mediated by exosome-like vesicles. Am J Respir Cell Mol Biol. 2019;60:209–20.PubMedPubMedCentral
44.
Lieschke GJ, Grail D, Hodgson G, Metcalf D, Stanley E, Cheers C, Fowler KJ, Basu S, Zhan YF, Dunn AR. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood. 1994;84:1737–46.PubMed
45.
Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, Cosmi L, Lunardi C, Annunziato F, Romagnani S, Cassatella MA. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood. 2010;115:335–43.PubMed
46.
Guo FH, Comhair SA, Zheng S, Dweik RA, Eissa NT, Thomassen MJ, Calhoun W, Erzurum SC. Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis. J Immunol. 2000;164:5970–80.PubMed
47.
Shiobara T, Chibana K, Watanabe T, Arai R, Horigane Y, Nakamura Y, Hayashi Y, Shimizu Y, Takemasa A, Ishii Y. Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells. Respir Res. 2016;17:28.PubMedPubMedCentral
48.
Ogawa Y, Kanai-Azuma M, Akimoto Y, Kawakami H, Yanoshita R. Exosome-like vesicles with dipeptidyl peptidase IV in human saliva. Biol Pharm Bull. 2008;31:1059–62.PubMed
49.
Kvarnhammar AM, Rydberg C, Jarnkrants M, Eriksson M, Uddman R, Benson M, Cardell LO. Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines. Respir Res. 2012;13:2.PubMedPubMedCentral
50.
Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78:2791–808.PubMed
51.
Shikotra A, Choy DF, Siddiqui S, Arthur G, Nagarkar DR, Jia G, Wright AK, Ohri CM, Doran E, Butler CA, et al. A CEACAM6-high airway neutrophil phenotype and CEACAM6-high epithelial cells are features of severe asthma. J Immunol. 2017;198:3307–17.PubMed
Metadata
Title
T2 and T17 cytokines alter the cargo and function of airway epithelium-derived extracellular vesicles
Authors
Elisabeth Ax
Zala Jevnikar
Aleksander Cvjetkovic
Carina Malmhäll
Henric Olsson
Madeleine Rådinger
Cecilia Lässer
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2020
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-020-01402-3

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