Dendritic cell exosome‑shuttled miRNA146a regulates exosome‑induced endothelial cell inflammation by inhibiting IRAK‑1: A feedback control mechanism

Zhong,Xin; Gao,Wei; Wu,Runda; Liu,Haibo; Ge,Junbo

doi:10.3892/mmr.2019.10749

Dendritic cell exosome‑shuttled miRNA146a regulates exosome‑induced endothelial cell inflammation by inhibiting IRAK‑1: A feedback control mechanism

Authors:
- Xin Zhong
- Wei Gao
- Runda Wu
- Haibo Liu
- Junbo Ge
View Affiliations

Affiliations: Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, P.R. China, Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
Published online on: October 16, 2019 https://doi.org/10.3892/mmr.2019.10749
Pages: 5315-5323

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Activation of endothelial cells is the first step of atherosclerosis. The current authors have previously reported that exosomes from mature dendritic cells (mDC‑exo) participate in endothelial inflammation and atherosclerosis through membrane tumor necrosis factor‑α mediated the nuclear factor (NF)‑κB signaling pathway. However, whether mDC‑exo shuttled microRNAs (miRNAs/miRs) play a role in endothelial inflammation remains unknown. In this study, mDC‑exo were co‑cultured with human umbilical vein endothelial cells (HUVECs) and the expression of adhesion molecules, such as vascular cell adhesion molecule‑1, intercellular adhesion molecule‑1 and E‑Selectin was investigated. Then the expression of miRNAs in DC‑exo was explored and the role of miR‑146a in endothelial inflammation was investigated. mDC‑exos were first demonstrated to increase endothelial expression of adhesion molecules through a quick activation of the NF‑κB signaling pathway. Then it was demonstrated that HUVECs resistant to a second stimulation after the first stimulation by mDC‑exo. A set of miRNAs were targeted and their expression in HUVECs stimulated with mDC‑exo was measured. Finally, it was confirmed that mDC‑exo shuttles miR‑146a into HUVECs and the shuttled miR‑146a contributes to protect HUVECs from a second stimulation through inhibiting interleukin‑1 receptor‑associated kinase. These data suggest a negative feedback loop of inflammation regulation by DC‑exo.

View Figures

View References

1	Hopkins PN: Molecular biology of atherosclerosis. Physiol Rev. 93:1317–1542. 2013. View Article : Google Scholar : PubMed/NCBI
2	Zernecke A: Dendritic cells in atherosclerosis: Evidence in mice and humans. Arterioscler Thromb Vasc Biol. 35:763–770. 2015. View Article : Google Scholar : PubMed/NCBI
3	Koltsova EK and Ley K: How dendritic cells shape atherosclerosis. Trends Immunol. 32:540–547. 2011. View Article : Google Scholar : PubMed/NCBI
4	Millonig G, Niederegger H, Rabl W, Hochleitner BW, Hoefer D, Romani N and Wick G: Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler Thromb Vasc Biol. 21:503–508. 2001. View Article : Google Scholar : PubMed/NCBI
5	Yilmaz A, Lochno M, Traeg F, Cicha I, Reiss C, Stumpf C, Raaz D, Anger T, Amann K, Probst T, et al: Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques. Atherosclerosis. 176:101–110. 2004. View Article : Google Scholar : PubMed/NCBI
6	Busch M, Westhofen TC, Koch M, Lutz MB and Zernecke A: Dendritic cell subset distributions in the aorta in healthy and atherosclerotic mice. PLoS One. 9:e884522014. View Article : Google Scholar : PubMed/NCBI
7	Choi JH, Cheong C, Dandamudi DB, Park CG, Rodriguez A, Mehandru S, Velinzon K, Jung IH, Yoo JY, Oh GT and Steinman RM and Steinman RM: Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity. 35:819–831. 2011. View Article : Google Scholar : PubMed/NCBI
8	Galkina E, Kadl A, Sanders J, Varughese D, Sarembock IJ and Ley K: Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med. 203:1273–1282. 2006. View Article : Google Scholar : PubMed/NCBI
9	Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, et al: Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 4:270662015. View Article : Google Scholar : PubMed/NCBI
10	Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, Seabra MC, Round JL, Ward DM and O'Connell RM: Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 6:73212015. View Article : Google Scholar : PubMed/NCBI
11	Munich S, Sobo-Vujanovic A, Buchser WJ, Beer-Stolz D and Vujanovic NL: Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands. Oncoimmunology. 1:1074–1083. 2012. View Article : Google Scholar : PubMed/NCBI
12	Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, et al: Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 119:756–766. 2012. View Article : Google Scholar : PubMed/NCBI
13	Gao W, Liu H, Yuan J, Wu C, Huang D, Ma Y, Zhu J, Ma L, Guo J, Shi H, et al: Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. J Cell Mol Med. 20:2318–2327. 2016. View Article : Google Scholar : PubMed/NCBI
14	Wu C, Gong Y, Yuan J, Zhang W, Zhao G, Li H, Sun A, KaiHu, Zou Y and Ge J: microRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos. J Lipid Res. 53:2355–2363. 2012. View Article : Google Scholar : PubMed/NCBI
15	Gatti E, Velleca MA, Biedermann BC, Ma W, Unternaehrer J, Ebersold MW, Medzhitov R, Pober JS and Mellman I: Large-scale culture and selective maturation of human Langerhans cells from granulocyte colony-stimulating factor-mobilized CD34+ progenitors. J Immunol. 164:3600–3607. 2000. View Article : Google Scholar : PubMed/NCBI
16	Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, et al: MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA. 109:E2110–E2116. 2012. View Article : Google Scholar : PubMed/NCBI
17	Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, Just A, Remke J, Zimmer K, Zeug A, et al: Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 124:2136–2146. 2014. View Article : Google Scholar : PubMed/NCBI
18	Li J, Liu K, Liu Y, Xu Y, Zhang F, Yang H, Liu J, Pan T, Chen J, Wu M, et al: Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity. Nat Immunol. 14:793–803. 2013. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Andreou I, Sun X, Stone PH, Edelman ER and Feinberg MW: miRNAs in atherosclerotic plaque initiation, progression, and rupture. Trends Mol Med. 21:307–318. 2015. View Article : Google Scholar : PubMed/NCBI
21	Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, Delgado-Olguin P, Cybulsky MI and Fish JE: MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med. 5:1017–1034. 2013. View Article : Google Scholar : PubMed/NCBI
22	Zhu N, Zhang D, Chen S, Liu X, Lin L, Huang X, Guo Z, Liu J, Wang Y, Yuan W and Qin Y: Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis. 215:286–293. 2011. View Article : Google Scholar : PubMed/NCBI
23	Suárez Y, Wang C, Manes TD and Pober JS: Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: Feedback control of inflammation. J Immunol. 184:21–25. 2010. View Article : Google Scholar : PubMed/NCBI
24	Taganov KD, Boldin MP, Chang KJ and Baltimore D: NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 103:12481–12486. 2006. View Article : Google Scholar : PubMed/NCBI
25	Park H, Huang X, Lu C, Cairo MS and Zhou X: MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem. 290:2831–2841. 2015. View Article : Google Scholar : PubMed/NCBI
26	Niessner A and Weyand CM: Dendritic cells in atherosclerotic disease. Clin Immunol. 134:25–32. 2010. View Article : Google Scholar : PubMed/NCBI
27	Galkina E and Ley K: Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol. 27:165–197. 2009. View Article : Google Scholar : PubMed/NCBI
28	Subramanian M, Thorp E, Hansson GK and Tabas I: Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest. 123:179–188. 2013. View Article : Google Scholar : PubMed/NCBI
29	Alberts-Grill N, Denning TL, Rezvan A and Jo H: The role of the vascular dendritic cell network in atherosclerosis. Am J Physiol Cell Physiol. 305:C1–C21. 2013. View Article : Google Scholar : PubMed/NCBI
30	Li Y, Shen Z and Yu XY: Transport of microRNAs via exosomes. Nat Rev Cardiol. 12:1982015. View Article : Google Scholar : PubMed/NCBI
31	Boon RA and Dimmeler S: MicroRNAs in myocardial infarction. Nat Rev Cardiol. 12:135–142. 2015. View Article : Google Scholar : PubMed/NCBI
32	Sahoo S and Losordo DW: Exosomes and cardiac repair after myocardial infarction. Circ Res. 114:333–344. 2014. View Article : Google Scholar : PubMed/NCBI
33	Economou EK, Oikonomou E, Siasos G, Papageorgiou N, Tsalamandris S, Mourouzis K, Papaioanou S and Tousoulis D: The role of microRNAs in coronary artery disease: From pathophysiology to diagnosis and treatment. Atherosclerosis. 241:624–633. 2015. View Article : Google Scholar : PubMed/NCBI
34	Kumar S, Vijayan M, Bhatti JS and Reddy PH: MicroRNAs as peripheral biomarkers in aging and age-related diseases. Prog Mol Biol Transl Sci. 146:47–94. 2017. View Article : Google Scholar : PubMed/NCBI
35	Kumar S and Reddy PH: Are circulating microRNAs peripheral biomarkers for Alzheimer's disease? Biochim Biophys Acta. 1862:1617–1627. 2016. View Article : Google Scholar : PubMed/NCBI