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Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice

Lai, Niansheng, Wu, Degang, Liang, Tianyu, Pan, Pengjie, Yuan, Guiqiang, Li, Xiang, Li, Haiying, Shen, Haitao +2 more·2020·Journal of Neuroinflammation
DOI 10.1186/s12974-020-01745-0PMC PMC7041199
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Abstract

Background: Inflammation is a potential crucial factor in the pathogenesis of subarachnoid hemorrhage (SAH). Circulating microRNAs (miRNAs) are involved in the regulation of diverse aspects of neuronal dysfunction. The therapeutic potential of miRNAs has been demonstrated in several CNS disorders and is thought to involve modulation of neuroinflammation. Here, we found that peripherally injected modified exosomes (Exos) delivered miRNAs to the brains of mice with SAH and that the potential mechanism was regulated by regulation of neuroinflammation. Methods: Next-generation sequencing (NGS) and qRT-PCR were used to define the global miRNA profile of plasma exosomes in aSAH patients and healthy controls. We peripherally injected RVG/Exos/miR-193b-3p to achieve delivery of miR-193b-3p to the brain of mice with SAH. The effects of miR-193b-3p on SAH were assayed using a neurological score, brain water content, blood-brain barrier (BBB) injury, and Fluoro-Jade C (FJC) staining. Western blotting analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to measure various proteins and mRNA levels. Results: NGS and qRT-PCR revealed that four circulating exosomal miRNAs were differentially expressed. RVG/Exos exhibited improved targeting to the brains of SAH mice. MiR-193b-3p suppressed the expression and activity of HDAC3, upregulating the acetylation of NF-κB p65. Finally, miR-193b-3p treatment mitigated the neurological behavioral impairment, brain edema, BBB injury, and neurodegeneration induced by SAH, and reduced inflammatory cytokine expression in the brains of mice after SAH. Conclusions: Exos/miR-193b-3p treatment attenuated the inflammatory response by acetylation of the NF-κB p65 via suppressed expression and activity of HDAC3. These effects alleviated neurobehavioral impairments and neuroinflammation following SAH.

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  • Previous work on this cohort demonstrated that these samples are transcriptionally closer to postmortem human brain tissues than to tumor-associated profiles, suggesting minimal contamination.

    “Accordingly, our previous work on this cohort 78 demonstrated that these samples are transcriptionally closer to postmortem human brain tissues than to tumor-associated profiles, suggesting minimal contamination.”

    From Human brain microRNAs exhibit cell-type specificity and age dependence (2026) · cites this paper as [78]

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  1. [1]Vivancos J Gilo F Frutos R Maestre J Garcia-Pastor A Quintana F Roda JM Ximenez-Carrillo A Diez Tejedor E Fuentes B Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment Neurologia 2014 29 353 370 10.1016/j.nrl.2012.07.009 23044408 · DOI
  2. [2]Lai NS Zhang JQ Qin FY Sheng B Fang XG Li ZB Serum microRNAs are non-invasive biomarkers for the presence and progression of subarachnoid haemorrhage Biosci Rep 2017 37 28 PMC5322746 28115593
  3. [3]Sheng B Fang X Liu C Wu D Xia D Xu S Lai N Persistent high levels of miR-502-5p are associated with poor neurologic outcome in patients with aneurysmal subarachnoid hemorrhage World Neurosurg 2018 116 e92 e99 10.1016/j.wneu.2018.04.088 29689401 · DOI
  4. [4]Helbok R Schiefecker AJ Beer R Dietmann A Antunes AP Sohm F Fischer M Hackl WO Rhomberg P Lackner P Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study Crit Care 2015 19 75 10.1186/s13054-015-0809-9 25887441 PMC4384312 · DOI
  5. [5]Dou Y Shen H Feng D Li H Tian X Zhang J Wang Z Chen G Tumor necrosis factor receptor-associated factor 6 participates in early brain injury after subarachnoid hemorrhage in rats through inhibiting autophagy and promoting oxidative stress J Neurochem 2017 142 478 492 10.1111/jnc.14075 28543180 · DOI
  6. [6]Liu W Li R Yin J Guo S Chen Y Fan H Li G Li Z Li X Zhang X Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch J Neuroinflammation 2019 16 8 10.1186/s12974-019-1396-5 30646897 PMC6334441 · DOI
  7. [7]Lai NS Wu DG Fang XG Lin YC Chen SS Li ZB Xu SS Serum microRNA-210 as a potential noninvasive biomarker for the diagnosis and prognosis of glioma Br J Cancer 2015 112 1241 1246 10.1038/bjc.2015.91 25756397 PMC4385967 · DOI
  8. [8]Iranifar E Seresht BM Momeni F Fadaei E Mehr MH Ebrahimi Z Rahmati M Kharazinejad E Mirzaei H Exosomes and microRNAs: new potential therapeutic candidates in Alzheimer disease therapy J Cell Physiol 2019 234 2296 2305 10.1002/jcp.27214 30191975 · DOI
  9. [9]Roitbak T Silencing a multifunctional microRNA is beneficial for stroke recovery Front Mol Neurosci 2018 11 58 10.3389/fnmol.2018.00058 29527155 PMC5829058 · DOI
  10. [11]Yang J Zhang X Chen X Wang L Yang G Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia Mol Ther Nucleic Acids 2017 7 278 287 10.1016/j.omtn.2017.04.010 28624203 PMC5415550 · DOI
  11. [12]Sun L Zhang W Li Z Li M Guo J Wang H Wang X The expression of cerebrospinal fluid exosomal miR-630 plays an important role in the dysfunction of endothelial cells after subarachnoid hemorrhage Sci Rep 2019 9 019 48049 10.1038/s41598-018-37221-2 PMC6687820 31395931 · DOI
  12. [13]Bache S Rasmussen R Rossing M Laigaard FP Nielsen FC Moller K MicroRNA changes in cerebrospinal fluid after subarachnoid hemorrhage Stroke 2017 48 2391 2398 10.1161/STROKEAHA.117.017804 28768799 PMC5571886 · DOI
  13. [14]Sheng B, Lai NS, Yao Y, Dong J, Li ZB, Zhao XT, Liu JQ, Li XQ, Fang XG. Early serum miR-1297 is an indicator of poor neurological outcome in patients with aSAH. Biosci Rep. 2018;38:BSR20180646. PMC6246762 30355655
  14. [15]Zhang L Zhang S Yao J Lowery FJ Zhang Q Huang WC Li P Li M Wang X Zhang C Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth Nature 2015 527 100 104 10.1038/nature15376 26479035 PMC4819404 · DOI · Paper page
  15. [16]Ramirez SH Andrews AM Paul D Pachter JS Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers Fluids Barriers CNS 2018 15 018 0104 10.1186/s12987-018-0104-7 PMC6026502 29960602 · DOI
  16. [17]Kanninen KM Bister N Koistinaho J Malm T Exosomes as new diagnostic tools in CNS diseases Biochim Biophys Acta 1862 2016 403 410 26432482
  17. [18]Haney MJ Klyachko NL Zhao Y Gupta R Plotnikova EG He Z Patel T Piroyan A Sokolsky M Kabanov AV Batrakova EV Exosomes as drug delivery vehicles for Parkinson's disease therapy J Control Release 2015 207 18 30 10.1016/j.jconrel.2015.03.033 25836593 PMC4430381 · DOI · Paper page
  18. [19]Kim DK Nishida H An SY Shetty AK Bartosh TJ Prockop DJ Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI Proc Natl Acad Sci U S A 2016 113 170 175 10.1073/pnas.1522297113 26699510 PMC4711859 · DOI
  19. [20]Lang FM Hossain A Gumin J Momin EN Shimizu Y Ledbetter D Shahar T Yamashita S Parker Kerrigan B Fueyo J Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas Neuro-Oncology 2018 20 380 390 10.1093/neuonc/nox152 29016843 PMC5817945 · DOI
  20. [21]Tian T Zhang HX He CP Fan S Zhu YL Qi C Huang NP Xiao ZD Lu ZH Tannous BA Gao J Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy Biomaterials 2018 150 137 149 10.1016/j.biomaterials.2017.10.012 29040874 · DOI · Paper page
  21. [22]Chen J Chopp M Exosome therapy for stroke Stroke 2018 49 1083 1090 10.1161/STROKEAHA.117.018292 29669873 PMC6028936 · DOI
  22. [24]Deng W Kandhi S Zhang B Huang A Koller A Sun D Extravascular blood augments myogenic constriction of cerebral arterioles: implications for hemorrhage-induced vasospasm J Am Heart Assoc 2018 7 008623 PMC6015404 29654195
  23. [25]Cui GH Guo HD Li H Zhai Y Gong ZB Wu J Liu JS Dong YR Hou SX Liu JR RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer’s disease Immun Ageing 2019 16 10 10.1186/s12979-019-0150-2 31114624 PMC6515654 · DOI
  24. [26]Zou M, Huang W, Jiang W, Wu Y, Chen Q. Role of Cav-1 in HIV-1 Tat-induced dysfunction of tight junctions and Abeta-transferring proteins. Oxidative Med Cell Longev. 2019;14:3403206. PMC6537002 31217837
  25. [27]Garcia JH Wagner S Liu KF Hu XJ Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation Stroke 1995 26 627 634 10.1161/01.STR.26.4.627 7709410 · DOI
  26. [28]Liu FY Cai J Wang C Ruan W Guan GP Pan HZ Li JR Qian C Chen JS Wang L Chen G Fluoxetine attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage: a possible role for the regulation of TLR4/MyD88/NF-kappaB signaling pathway J Neuroinflammation 2018 15 347 10.1186/s12974-018-1388-x 30572907 PMC6302437 · DOI
  27. [29]Meng F Li Z Zhang Z Yang Z Kang Y Zhao X Long D Hu S Gu M He S MicroRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3 Theranostics 2018 8 2862 2883 10.7150/thno.23547 29774080 PMC5957014 · DOI
  28. [30]Kao MH Lin TN Histone deacetylases in stroke Chin J Physiol 2019 62 95 107 10.4103/CJP.CJP_22_19 31249263 · DOI
  29. [31]San José-Enériz Gimenez-Camino Agirre Prosper HDAC Inhibitors in Acute Myeloid Leukemia Cancers 2019 11 11 1794 10.3390/cancers11111794 31739588 PMC6896008 · DOI
  30. [32]Ziesche E Kettner-Buhrow D Weber A Wittwer T Jurida L Soelch J Muller H Newel D Kronich P Schneider H The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB Nucleic Acids Res 2013 41 90 109 10.1093/nar/gks916 23087373 PMC3592411 · DOI
  31. [33]Chen S Ye J Chen X Shi J Wu W Lin W Li Y Fu H Li S Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-kappaB pathway dependent of HDAC3 J Neuroinflammation 2018 15 018 1193 10.1186/s12974-017-1049-5 PMC5960086 29776446 · DOI
  32. [34]Alvarez-Erviti L Seow Y Yin H Betts C Lakhal S Wood MJ Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes Nat Biotechnol 2011 29 341 345 10.1038/nbt.1807 21423189 · DOI · Paper page
  33. [35]Casadei L Calore F Creighton CJ Guescini M Batte K Iwenofu OH Zewdu A Braggio DA Bill KL Fadda P Exosome-derived miR-25-3p and miR-92a-3p stimulate liposarcoma progression Cancer Res 2017 77 3846 3856 10.1158/0008-5472.CAN-16-2984 28588009 PMC6033276 · DOI
  34. [37]Shen H Yao X Li H Li X Zhang T Sun Q Ji C Chen G Role of exosomes derived from miR-133b modified MSCs in an experimental rat model of intracerebral hemorrhage J Mol Neurosci 2018 64 421 430 10.1007/s12031-018-1041-2 29455449 · DOI
  35. [38]Cooper JM Wiklander PB Nordin JZ Al-Shawi R Wood MJ Vithlani M Schapira AH Simons JP El-Andaloussi S Alvarez-Erviti L Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice Mov Disord 2014 29 1476 1485 10.1002/mds.25978 25112864 PMC4204174 · DOI
  36. [39]Reddy DS Wu X Golub VM Dashwood WM Dashwood RH Measuring histone deacetylase inhibition in the brain Curr Protoc Pharmacol 2018 81 e41 10.1002/cpph.41 29927058 PMC6019607 · DOI · Paper page
  37. [40]Cuadrado-Tejedor M, Perez-Gonzalez M, Garcia-Munoz C, Muruzabal D, Garcia-Barroso C, Rabal O, Segura V, Sanchez-Arias JA, Oyarzabal J, Garcia-Osta A. Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat Alzheimer’s disease. Front Aging Neurosci. 2019;11:149. PMC6597953 31281249
  38. [41]Siebzehnrubl FA Raber KA Urbach YK Schulze-Krebs A Canneva F Moceri S Habermeyer J Achoui D Gupta B Steindler DA Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition Proc Natl Acad Sci U S A 2018 115 E8765 E8774 10.1073/pnas.1807962115 30150378 PMC6140493 · DOI
  39. [42]Demyanenko S Neginskaya M Berezhnaya E Expression of class I histone deacetylases in ipsilateral and contralateral hemispheres after the focal photothrombotic infarction in the mouse brain Transl Stroke Res 2018 9 471 483 10.1007/s12975-017-0595-6 29218547 · DOI
  40. [43]McClure JJ Inks ES Zhang C Peterson YK Li J Chundru K Lee B Buchanan A Miao S Chou CJ Comparison of the deacylase and deacetylase activity of zinc-dependent HDACs ACS Chem Biol 2017 12 1644 1655 10.1021/acschembio.7b00321 28459537 PMC5567816 · DOI
  41. [44]Pawlowska E Szczepanska J Wisniewski K Tokarz P Jaskolski DJ Blasiak J NF-kappaB-mediated inflammation in the pathogenesis of intracranial aneurysm and subarachnoid hemorrhage. Does autophagy play a role? Int J Mol Sci 2018 19 E1245 10.3390/ijms19041245 29671828 PMC5979412 · DOI
  42. [45]You W Zuo G Shen H Tian X Li H Zhu H Yin J Zhang T Wang Z Potential dual role of nuclear factor-kappa B in experimental subarachnoid hemorrhage-induced early brain injury in rabbits Inflamm Res 2016 65 975 984 10.1007/s00011-016-0980-8 27554683 · DOI
  43. [46]Xue YL Zhang SX Zheng CF Li YF Zhang LH Hao YF Wang S Li XW Silencing of STAT4 protects against autoimmune myocarditis by regulating Th1/Th2 immune response via inactivation of the NF-kappaB pathway in rats Inflammation 2019 8 019 00978 30848408
  44. [47]Tian M Yang M Li Z Wang Y Chen W Yang L Li Y Yuan H Fluoxetine suppresses inflammatory reaction in microglia under OGD/R challenge via modulation of NF-kappaB signaling Biosci Rep 2019 39 30 PMC6487262 30944203
  45. [48]Liu T Yang T Xu Z Tan S Pan T Wan N Li S MicroRNA-193b-3p regulates hepatocyte apoptosis in selenium-deficient broilers by targeting MAML1 J Inorg Biochem 2018 186 235 245 10.1016/j.jinorgbio.2018.06.013 29990747 · DOI
  46. [49]Yang X Wu Q Zhang L Feng L Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in rats Front Mol Neurosci 2016 9 131 27965534 PMC5124709
  47. [50]Zhao B Yuan Q Hou JB Xia ZY Zhan LY Li M Jiang M Gao WW Liu L Inhibition of HDAC3 ameliorates cerebral ischemia reperfusion injury in diabetic mice in vivo and in vitro J Diabetes Res 2019 2019 8520856 30906786 PMC6393870
  48. [51]Zhao H Li G Zhang S Li F Wang R Tao Z Ma Q Han Z Yan F Fan J Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke J Cereb Blood Flow Metab 2019 39 2392 2405 10.1177/0271678X19875201 31510852 PMC6893973 · DOI
  49. [52]Langley B Brochier C Rivieccio MA Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke Stroke 2009 40 2899 2905 10.1161/STROKEAHA.108.540229 19478231 · DOI

Cited by

Sorted by citations

Authors
Lai, N., Wu, D., Liang, T., Pan, P., Yuan, G., Li, X., Li, H., Shen, H., Wang, Z., & Chen, G.
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2020-02-25
Volume
17
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-020-01745-0
PMC
PMC7041199
Cited by
171
References
3
Language
en
Licence
Funders
  • National Key R&D Program of China (No. 2018YFC1312600 and 2018YFC1312601)
  • National Natural Science Foundation of China (81701357)
  • Natural Science Foundation of Anhui Province (1708085QH181)
  • Project of Jiangsu Provincial Medical Innovation Team (CXTDA2017003)
  • Jiangsu Provincial Medical Youth Talent (QNRC2016728)
  • Suzhou Key Medical Centre (Szzx201501)
  • Scientific Department of Jiangsu Province (BE2017656)
  • Suzhou Government (LCZX201601)

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