Skip to main content
Top
Published in: Respiratory Research 1/2022

Open Access 01-12-2022 | Bronchial Asthma | Research

MiR-493-5p inhibits Th9 cell differentiation in allergic asthma by targeting FOXO1

Authors: Xingyu Rao, Heting Dong, Weili Zhang, Huiming Sun, Wenjing Gu, Xinxing Zhang, Li Huang, Yongdong Yan, Chuangli Hao, Wei Ji, Canhong Zhu, Zhengrong Chen

Published in: Respiratory Research | Issue 1/2022

Login to get access

Abstract

The role of micro RNAs (miRNAs) in asthma remains unclear. In this study, we examined the role of miRNA in targeting FOXO1 in asthma. Results showed that miR-493-5p was one of the differentially expressed miRNAs in the PBMCs of asthmatic children, and was also associated with Th cell differentiation. The miR-493-5p expression decreased significantly in the OVA-induced asthma mice than the control groups. The miR-493-5p mimic inhibited the expression of the IL-9, IRF4 and FOXO1, while the inhibitor restored these effects. Moreover, the Dual-Luciferase analysis results showed FOXO1 as a novel valid target of miR-493-5p. According to the rescue experiment, miR-493-5p inhibited Th9 cell differentiation by targeting FOXO1. Then the exosomes in association with the pathogenesis of asthma was identified. Various inflammatory cells implicated in asthmatic processes including B and T lymphocytes, DCs, mast cells, and epithelial cells can release exosomes. Our results demonstrated that the DC-derived exosomes can inhibit Th9 cell differentiation through miR-493-5p, thus DC-derived exosomal miR-493-5p/FOXO1/Th9 may serve as a potential therapeutic target in the development of asthma.
Appendix
Available only for authorised users
Literature
1.
go back to reference Coquet JM. A singular role for interleukin-9 in the development of asthma. Sci Immunol. 2020;5(48):eabc4021.CrossRef Coquet JM. A singular role for interleukin-9 in the development of asthma. Sci Immunol. 2020;5(48):eabc4021.CrossRef
2.
go back to reference Koch S, Sopel N, Finotto S. Th9 and other IL-9-producing cells in allergic asthma. Semin Immunopathol. 2017;39(1):55–68.CrossRef Koch S, Sopel N, Finotto S. Th9 and other IL-9-producing cells in allergic asthma. Semin Immunopathol. 2017;39(1):55–68.CrossRef
3.
go back to reference Angkasekwinai P. Th9 cells in allergic disease. Curr Allergy Asthma Rep. 2019;19(5):29.CrossRef Angkasekwinai P. Th9 cells in allergic disease. Curr Allergy Asthma Rep. 2019;19(5):29.CrossRef
4.
go back to reference Campos Carrascosa L, Klein M, Kitagawa Y, et al. Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4. Nat Commun. 2017;8:15366.CrossRef Campos Carrascosa L, Klein M, Kitagawa Y, et al. Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4. Nat Commun. 2017;8:15366.CrossRef
5.
go back to reference Lujambio A, Lowe SW. The microcosmos of cancer. Nature. 2012;482(7385):347–55.CrossRef Lujambio A, Lowe SW. The microcosmos of cancer. Nature. 2012;482(7385):347–55.CrossRef
6.
go back to reference Buttrick TS, Wang W, Yung C, et al. Foxo1 promotes Th9 cell differentiation and airway allergy. Sci Rep. 2018;8(1):818.CrossRef Buttrick TS, Wang W, Yung C, et al. Foxo1 promotes Th9 cell differentiation and airway allergy. Sci Rep. 2018;8(1):818.CrossRef
7.
go back to reference Denzer K, Kleijmeer MJ, Heijnen HF, et al. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113(Pt 19):3365–74.CrossRef Denzer K, Kleijmeer MJ, Heijnen HF, et al. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113(Pt 19):3365–74.CrossRef
8.
go back to reference Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.CrossRef Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.CrossRef
9.
go back to reference Alvarez-Erviti L, Seow Y, Yin H, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.CrossRef Alvarez-Erviti L, Seow Y, Yin H, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.CrossRef
10.
go back to reference Sun D, Zhuang X, Zhang S, et al. Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv Drug Deliv Rev. 2013;65(3):342–7.CrossRef Sun D, Zhuang X, Zhang S, et al. Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv Drug Deliv Rev. 2013;65(3):342–7.CrossRef
11.
go back to reference El Andaloussi S, Lakhal S, Mager I, et al. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev. 2013;65(3):391–7.CrossRef El Andaloussi S, Lakhal S, Mager I, et al. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev. 2013;65(3):391–7.CrossRef
12.
go back to reference Sastre B, Canas JA, Rodrigo-Munoz JM, et al. Novel modulators of asthma and allergy: exosomes and MicroRNAs. Front Immunol. 2017;8:826.CrossRef Sastre B, Canas JA, Rodrigo-Munoz JM, et al. Novel modulators of asthma and allergy: exosomes and MicroRNAs. Front Immunol. 2017;8:826.CrossRef
13.
go back to reference Thery C, Duban L, Segura E, et al. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. 2002;3(12):1156–62.CrossRef Thery C, Duban L, Segura E, et al. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. 2002;3(12):1156–62.CrossRef
14.
go back to reference Rajan S, Gogtay NJ, Konwar M, et al. The global initiative for asthma guidelines (2019): change in the recommendation for the management of mild asthma based on the SYGMA-2 trial—a critical appraisal. Lung India. 2020;37(2):169–73.CrossRef Rajan S, Gogtay NJ, Konwar M, et al. The global initiative for asthma guidelines (2019): change in the recommendation for the management of mild asthma based on the SYGMA-2 trial—a critical appraisal. Lung India. 2020;37(2):169–73.CrossRef
15.
go back to reference Kim JS, Kim WS, Choi HG, et al. Mycobacterium tuberculosis RpfB drives Th1-type T cell immunity via a TLR4-dependent activation of dendritic cells. J Leukoc Biol. 2013;94(4):733–49.CrossRef Kim JS, Kim WS, Choi HG, et al. Mycobacterium tuberculosis RpfB drives Th1-type T cell immunity via a TLR4-dependent activation of dendritic cells. J Leukoc Biol. 2013;94(4):733–49.CrossRef
16.
go back to reference Thery C, Amigorena S, Raposo G, et al. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol, 2006, Chapter 3: Unit 3 22. Thery C, Amigorena S, Raposo G, et al. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol, 2006, Chapter 3: Unit 3 22.
17.
go back to reference Lloyd CM, Saglani S. Opening the window of immune opportunity: treating childhood asthma. Trends Immunol. 2019;40(9):786–98.CrossRef Lloyd CM, Saglani S. Opening the window of immune opportunity: treating childhood asthma. Trends Immunol. 2019;40(9):786–98.CrossRef
18.
go back to reference Dechene L. TH1/TH2 immune response. J Allergy Clin Immunol. 2002;110(3):539–40 (author reply 540).CrossRef Dechene L. TH1/TH2 immune response. J Allergy Clin Immunol. 2002;110(3):539–40 (author reply 540).CrossRef
19.
go back to reference Muehling LM, Lawrence MG, Woodfolk JA. Pathogenic CD4(+) T cells in patients with asthma. J Allergy Clin Immunol. 2017;140(6):1523–40.CrossRef Muehling LM, Lawrence MG, Woodfolk JA. Pathogenic CD4(+) T cells in patients with asthma. J Allergy Clin Immunol. 2017;140(6):1523–40.CrossRef
20.
go back to reference Walker JA, Mckenzie ANJ. TH2 cell development and function. Nat Rev Immunol. 2018;18(2):121–33.CrossRef Walker JA, Mckenzie ANJ. TH2 cell development and function. Nat Rev Immunol. 2018;18(2):121–33.CrossRef
21.
go back to reference Dardalhon V, Awasthi A, Kwon H, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008;9(12):1347–55.CrossRef Dardalhon V, Awasthi A, Kwon H, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008;9(12):1347–55.CrossRef
22.
go back to reference Jia L, Wang Y, Li J, et al. Detection of IL-9 producing T cells in the PBMCs of allergic asthmatic patients. BMC Immunol. 2017;18(1):38.CrossRef Jia L, Wang Y, Li J, et al. Detection of IL-9 producing T cells in the PBMCs of allergic asthmatic patients. BMC Immunol. 2017;18(1):38.CrossRef
23.
go back to reference Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol. 2015;15(5):295–307.CrossRef Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol. 2015;15(5):295–307.CrossRef
24.
go back to reference Neurath MF, Finotto S. IL-9 signaling as key driver of chronic inflammation in mucosal immunity. Cytokine Growth Factor Rev. 2016;29:93–9.CrossRef Neurath MF, Finotto S. IL-9 signaling as key driver of chronic inflammation in mucosal immunity. Cytokine Growth Factor Rev. 2016;29:93–9.CrossRef
25.
go back to reference Hastie AT, Steele C, Dunaway CW, et al. Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma. Clin Exp Allergy. 2018;48(7):787–97.CrossRef Hastie AT, Steele C, Dunaway CW, et al. Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma. Clin Exp Allergy. 2018;48(7):787–97.CrossRef
26.
go back to reference Tong R, Xu L, Liang L, et al. Analysis of the levels of Th9 cells and cytokines in the peripheral blood of mice with bronchial asthma. Exp Ther Med. 2018;15(3):2480–4.PubMedPubMedCentral Tong R, Xu L, Liang L, et al. Analysis of the levels of Th9 cells and cytokines in the peripheral blood of mice with bronchial asthma. Exp Ther Med. 2018;15(3):2480–4.PubMedPubMedCentral
27.
go back to reference Veldhoen M, Uyttenhove C, Van Snick J, et al. Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9(12):1341–6.CrossRef Veldhoen M, Uyttenhove C, Van Snick J, et al. Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9(12):1341–6.CrossRef
28.
go back to reference Staudt V, Bothur E, Klein M, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity. 2010;33(2):192–202.CrossRef Staudt V, Bothur E, Klein M, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity. 2010;33(2):192–202.CrossRef
29.
go back to reference Lee WH, Jang SW, Kim HS, et al. BATF3 is sufficient for the induction of Il9 expression and can compensate for BATF during Th9 cell differentiation. Exp Mol Med. 2019;51(11):1–12.PubMedPubMedCentral Lee WH, Jang SW, Kim HS, et al. BATF3 is sufficient for the induction of Il9 expression and can compensate for BATF during Th9 cell differentiation. Exp Mol Med. 2019;51(11):1–12.PubMedPubMedCentral
30.
go back to reference Milger K, Gotschke J, Krause L, et al. Identification of a plasma miRNA biomarker signature for allergic asthma: a translational approach. Allergy. 2017;72(12):1962–71.CrossRef Milger K, Gotschke J, Krause L, et al. Identification of a plasma miRNA biomarker signature for allergic asthma: a translational approach. Allergy. 2017;72(12):1962–71.CrossRef
31.
go back to reference Li J, Panganiban R, Kho AT, et al. Circulating MicroRNAs and treatment response in childhood asthma. Am J Respir Crit Care Med. 2020;202(1):65–72.CrossRef Li J, Panganiban R, Kho AT, et al. Circulating MicroRNAs and treatment response in childhood asthma. Am J Respir Crit Care Med. 2020;202(1):65–72.CrossRef
32.
go back to reference Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015;77:13–27.CrossRef Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015;77:13–27.CrossRef
33.
go back to reference Budnik V, Ruiz-Canada C, Wendler F. Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci. 2016;17(3):160–72.CrossRef Budnik V, Ruiz-Canada C, Wendler F. Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci. 2016;17(3):160–72.CrossRef
34.
go back to reference Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.CrossRef Valadi H, Ekstrom K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.CrossRef
35.
go back to reference Canas JA, Sastre B, Mazzeo C, et al. Exosomes from eosinophils autoregulate and promote eosinophil functions. J Leukoc Biol. 2017;101(5):1191–9.CrossRef Canas JA, Sastre B, Mazzeo C, et al. Exosomes from eosinophils autoregulate and promote eosinophil functions. J Leukoc Biol. 2017;101(5):1191–9.CrossRef
36.
go back to reference Vargas A, Roux-Dalvai F, Droit A, et al. Neutrophil-derived exosomes: a new mechanism contributing to airway smooth muscle remodeling. Am J Respir Cell Mol Biol. 2016;55(3):450–61.CrossRef Vargas A, Roux-Dalvai F, Droit A, et al. Neutrophil-derived exosomes: a new mechanism contributing to airway smooth muscle remodeling. Am J Respir Cell Mol Biol. 2016;55(3):450–61.CrossRef
37.
go back to reference Okoye IS, Coomes SM, Pelly VS, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41(1):89–103.CrossRef Okoye IS, Coomes SM, Pelly VS, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41(1):89–103.CrossRef
38.
go back to reference Huang L, Zhang X, Wang M, et al. Exosomes from thymic stromal lymphopoietin-activated dendritic cells promote Th2 differentiation through the OX40 ligand. Pathobiology. 2019;86(2–3):111–7.CrossRef Huang L, Zhang X, Wang M, et al. Exosomes from thymic stromal lymphopoietin-activated dendritic cells promote Th2 differentiation through the OX40 ligand. Pathobiology. 2019;86(2–3):111–7.CrossRef
39.
go back to reference Besnard AG, Togbe D, Guillou N, et al. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol. 2011;41(6):1675–86.CrossRef Besnard AG, Togbe D, Guillou N, et al. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol. 2011;41(6):1675–86.CrossRef
40.
go back to reference Rank MA, Kobayashi T, Kozaki H, et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009;123(5):1047–54.CrossRef Rank MA, Kobayashi T, Kozaki H, et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009;123(5):1047–54.CrossRef
Metadata
Title
MiR-493-5p inhibits Th9 cell differentiation in allergic asthma by targeting FOXO1
Authors
Xingyu Rao
Heting Dong
Weili Zhang
Huiming Sun
Wenjing Gu
Xinxing Zhang
Li Huang
Yongdong Yan
Chuangli Hao
Wei Ji
Canhong Zhu
Zhengrong Chen
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-02207-2

Other articles of this Issue 1/2022

Respiratory Research 1/2022 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.