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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

01-12-2020 | Subarachnoid Hemorrhage | Research

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

Authors: Niansheng Lai, Degang Wu, Tianyu Liang, Pengjie Pan, Guiqiang Yuan, Xiang Li, Haiying Li, Haitao Shen, Zhong Wang, Gang Chen

Published in: Journal of Neuroinflammation | Issue 1/2020

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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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Literature
1.
Vivancos J, Gilo F, Frutos R, Maestre J, Garcia-Pastor A, Quintana F, Roda JM, Ximenez-Carrillo A, Diez Tejedor E, Fuentes B, et al. Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment. Neurologia. 2014;29:353–70.PubMedCrossRef
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.
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:e92–9.PubMedCrossRef
4.
Helbok R, Schiefecker AJ, Beer R, Dietmann A, Antunes AP, Sohm F, Fischer M, Hackl WO, Rhomberg P, Lackner P, et al. Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study. Crit Care. 2015;19:75.PubMedPubMedCentralCrossRef
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;142:478–92.PubMedCrossRef
6.
Liu W, Li R, Yin J, Guo S, Chen Y, Fan H, Li G, Li Z, Li X, Zhang X, et al. 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.PubMedPubMedCentralCrossRef
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;112:1241–6.PubMedPubMedCentralCrossRef
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;234:2296–305.PubMedCrossRef
9.
10.
Ge X, Li W, Huang S, Yin Z, Yang M, Han Z, Chen F, Wang H, Lei P, Zhang JN. Increased miR-21-3p in injured brain microvascular endothelial cells following traumatic brain injury aggravates blood-brain barrier damage by promoting cellular apoptosis and inflammation through targeting MAT2B. J Neurotrauma. 2018. https://​doi.​org/​10.​1089/​neu.​2018.​5728.PubMedCrossRef
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;7:278–87.PubMedPubMedCentralCrossRef
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.CrossRef
13.
Bache S, Rasmussen R, Rossing M, Laigaard FP, Nielsen FC, Moller K. MicroRNA changes in cerebrospinal fluid after subarachnoid hemorrhage. Stroke. 2017;48:2391–8.PubMedPubMedCentralCrossRef
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.
15.
Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527:100–4.PubMedPubMedCentralCrossRef
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.CrossRef
17.
Kanninen KM, Bister N, Koistinaho J, Malm T. Exosomes as new diagnostic tools in CNS diseases. Biochim Biophys Acta. 1862;2016:403–10.
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.PubMedPubMedCentralCrossRef
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;113:170–5.PubMedCrossRef
20.
Lang FM, Hossain A, Gumin J, Momin EN, Shimizu Y, Ledbetter D, Shahar T, Yamashita S, Parker Kerrigan B, Fueyo J, et al. Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas. Neuro-Oncology. 2018;20:380–90.PubMedCrossRef
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;150:137–49.PubMedCrossRef
22.
23.
Fu C, Xiang Y, Li X, Fu A. Targeted transport of nanocarriers into brain for theranosis with rabies virus glycoprotein-derived peptide. Mater Sci Eng C Mater Biol Appl. 2018;87:155–66.PubMedCrossRef
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.
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.PubMedPubMedCentralCrossRef
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.
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;26:627–34.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
29.
Meng F, Li Z, Zhang Z, Yang Z, Kang Y, Zhao X, Long D, Hu S, Gu M, He S, et al. MicroRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3. Theranostics. 2018;8:2862–83.PubMedPubMedCentralCrossRef
30.
31.
32.
Ziesche E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, Muller H, Newel D, Kronich P, Schneider H, et al. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB. Nucleic Acids Res. 2013;41:90–109.PubMedCrossRef
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.CrossRef
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;29:341–5.PubMedCrossRef
35.
Casadei L, Calore F, Creighton CJ, Guescini M, Batte K, Iwenofu OH, Zewdu A, Braggio DA, Bill KL, Fadda P, et al. Exosome-derived miR-25-3p and miR-92a-3p stimulate liposarcoma progression. Cancer Res. 2017;77:3846–56.PubMedPubMedCentralCrossRef
36.
Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750.
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;64:421–30.PubMedCrossRef
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;29:1476–85.PubMedPubMedCentralCrossRef
39.
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.
41.
Siebzehnrubl FA, Raber KA, Urbach YK, Schulze-Krebs A, Canneva F, Moceri S, Habermeyer J, Achoui D, Gupta B, Steindler DA, et al. 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:E8765–74.PubMedPubMedCentralCrossRef
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;9:471–83.PubMedCrossRef
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;12:1644–55.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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;65:975–84.PubMedCrossRef
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.
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.
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;186:235–45.PubMedCrossRef
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.PubMedPubMedCentral
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.PubMedPubMedCentral
51.
Zhao H, Li G, Zhang S, Li F, Wang R, Tao Z, Ma Q, Han Z, Yan F, Fan J, et al. Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke. J Cereb Blood Flow Metab. 2019;39:2392–405.PubMedCrossRefPubMedCentral
52.
Langley B, Brochier C, Rivieccio MA. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke. 2009;40:2899–905.PubMedCrossRef
Metadata
Title
Systemic exosomal miR-193b-3p delivery attenuates neuroinflammation in early brain injury after subarachnoid hemorrhage in mice
Authors
Niansheng Lai
Degang Wu
Tianyu Liang
Pengjie Pan
Guiqiang Yuan
Xiang Li
Haiying Li
Haitao Shen
Zhong Wang
Gang Chen
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-020-01745-0

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