Abstract
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality among the world, while the advance of TBI management is rather limited in recent years. The deregulation of microRNAs (miRNAs) has been widely reported in TBI patients and animal models, and certain miRNAs have been identified as the emerging biomarkers of TBI. However, the role of miRNAs in the regulatory mechanism of TBI remains unclear. To demonstrate the effect of miR-146a mimic on TBI-induced neural damages, TBI mouse model was constructed by cortical impact injury (CCI). The chemokine levels were examined by ELISA assays. Behavioral experiments were used to estimate the impact of miR-146a mimics on neurological functions in mice. Western blot assays were performed to demonstrate the protein levels. qRT-PCR assays were utilized to investigate the expression alteration of RNA levels. It was found that miR-146a was upregulated both in brain and serum in TBI mice. miR-146a mimic downregulated inflammatory cytokines secretion in mouse brain. The NF-κB signaling pathway was inhibited by miR-146a mimic. miR-146a treatment attenuated the impact caused by TBI to mouse brain and improve the long-term neurological function. In conclusion, miR-146a mimics ameliorate TBI-related injuries via JNK and NF-κB signaling pathway.
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References
Atif, H., & Hicks, S. D. (2019). A review of microRNA biomarkers in traumatic brain injury. Journal of Experimental Neuroscience, 13, 1179069519832286. https://doi.org/10.1177/1179069519832286.
Barry, G. (2014). Integrating the roles of long and small non-coding RNA in brain function and disease. Molecular Psychiatry, 19(4), 410–416. https://doi.org/10.1038/mp.2013.196.
Bhomia, M., Balakathiresan, N. S., Wang, K. K., Papa, L., & Maheshwari, R. K. (2016). A panel of serum miRNA biomarkers for the diagnosis of severe to mild traumatic brain injury in humans. Scientific Reports, 6, 28148. https://doi.org/10.1038/srep28148.
Bhowmick, S., D'Mello, V., Caruso, D., & Abdul-Muneer, P. M. (2019). Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death. Journal of Molecular Medicine, 97(12), 1627–1641. https://doi.org/10.1007/s00109-019-01851-4.
Brazinova, A., Rehorcikova, V., Taylor, M. S., Buckova, V., Majdan, M., Psota, M., et al. (2018). Epidemiology of traumatic brain injury in Europe: A living systematic review. Journal of Neurotrauma. https://doi.org/10.1089/neu.2015.4126.
Bruns, J., Jr., & Hauser, W. A. (2003). The epidemiology of traumatic brain injury: A review. Epilepsia, 44(s10), 2–10. https://doi.org/10.1046/j.1528-1157.44.s10.3.x.
Chang, V. C., Guerriero, E. N., & Colantonio, A. (2015). Epidemiology of work-related traumatic brain injury: A systematic review. American Journal of Industrial Medicine, 58(4), 353–377. https://doi.org/10.1002/ajim.22418.
Danborg, P. B., Simonsen, A. H., Waldemar, G., & Heegaard, N. H. (2014). The potential of microRNAs as biofluid markers of neurodegenerative diseases—A systematic review. Biomarkers, 19(4), 259–268. https://doi.org/10.3109/1354750X.2014.904001.
DeKosky, S. T., & Asken, B. M. (2017). Injury cascades in TBI-related neurodegeneration. Brain Injury, 31(9), 1177–1182. https://doi.org/10.1080/02699052.2017.1312528.
Dewan, M. C., Mummareddy, N., Wellons, J. C., 3rd, & Bonfield, C. M. (2016). Epidemiology of global pediatric traumatic brain injury: Qualitative review. World Neurosurgery, 91(497–509), e491. https://doi.org/10.1016/j.wneu.2016.03.045.
Dinet, V., Petry, K. G., & Badaut, J. (2019). Brain-immune interactions and neuroinflammation after traumatic brain injury. Frontiers in Neuroscience, 13, 1178. https://doi.org/10.3389/fnins.2019.01178.
Ferreira, A. P., Rodrigues, F. S., Della-Pace, I. D., Mota, B. C., Oliveira, S. M., Velho Gewehr, C., et al. (2013). The effect of NADPH-oxidase inhibitor apocynin on cognitive impairment induced by moderate lateral fluid percussion injury: Role of inflammatory and oxidative brain damage. Neurochemistry International, 63(6), 583–593. https://doi.org/10.1016/j.neuint.2013.09.012.
Ginhoux, F., Lim, S., Hoeffel, G., Low, D., & Huber, T. (2013). Origin and differentiation of microglia. Frontiers in Cellular Neuroscience, 7, 45. https://doi.org/10.3389/fncel.2013.00045.
Harrison, E. B., Hochfelder, C. G., Lamberty, B. G., Meays, B. M., Morsey, B. M., Kelso, M. L., et al. (2016). Traumatic brain injury increases levels of miR-21 in extracellular vesicles: Implications for neuroinflammation. FEBS Open Bio, 6(8), 835–846. https://doi.org/10.1002/2211-5463.12092.
Hicks, S. D., Johnson, J., Carney, M. C., Bramley, H., Olympia, R. P., Loeffert, A. C., et al. (2018). Overlapping microRNA expression in saliva and cerebrospinal fluid accurately identifies pediatric traumatic brain injury. Journal of Neurotrauma, 35(1), 64–72. https://doi.org/10.1089/neu.2017.5111.
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017). Neuroimmunology of traumatic brain injury: Time for a paradigm shift. Neuron, 95(6), 1246–1265. https://doi.org/10.1016/j.neuron.2017.07.010.
Johnson, J. J., Loeffert, A. C., Stokes, J., Olympia, R. P., Bramley, H., & Hicks, S. D. (2018). Association of salivary microRNA changes with prolonged concussion symptoms. JAMA Pediatrics, 172(1), 65–73. https://doi.org/10.1001/jamapediatrics.2017.3884.
Kokiko-Cochran, O., Ransohoff, L., Veenstra, M., Lee, S., Saber, M., Sikora, M., et al. (2016). Altered neuroinflammation and behavior after traumatic brain injury in a mouse model of Alzheimer's disease. Journal of Neurotrauma, 33(7), 625–640. https://doi.org/10.1089/neu.2015.3970.
Lasry, O., Liu, E. Y., Powell, G. A., Ruel-Laliberte, J., Marcoux, J., & Buckeridge, D. L. (2017). Epidemiology of recurrent traumatic brain injury in the general population: A systematic review. Neurology, 89(21), 2198–2209. https://doi.org/10.1212/WNL.0000000000004671.
Lozano, D., Gonzales-Portillo, G. S., Acosta, S., de la Pena, I., Tajiri, N., Kaneko, Y., et al. (2015). Neuroinflammatory responses to traumatic brain injury: Etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatric Disease and Treatment, 11, 97–106. https://doi.org/10.2147/NDT.S65815.
Masson, F., Thicoipe, M., Aye, P., Mokni, T., Senjean, P., Schmitt, V., et al. (2001). Epidemiology of severe brain injuries: A prospective population-based study. Journal of Trauma, 51(3), 481–489. https://doi.org/10.1097/00005373-200109000-00010.
Miao, W., Bao, T. H., Han, J. H., Yin, M., Yan, Y., Wang, W. W., et al. (2015). Voluntary exercise prior to traumatic brain injury alters miRNA expression in the injured mouse cerebral cortex. Brazilian Journal of Medical and Biological Research, 48(5), 433–439. https://doi.org/10.1590/1414-431X20144012.
Ng, S. Y., & Lee, A. Y. W. (2019). Traumatic brain injuries: Pathophysiology and potential therapeutic targets. Frontiers in Cellular Neuroscience, 13, 528. https://doi.org/10.3389/fncel.2019.00528.
Pan, Y. B., Sun, Z. L., & Feng, D. F. (2017). The role of microRNA in traumatic brain injury. Neuroscience, 367, 189–199. https://doi.org/10.1016/j.neuroscience.2017.10.046.
Paterson, M. R., & Kriegel, A. J. (2017). miR-146a/b: A family with shared seeds and different roots. Physiological Genomics, 49(4), 243–252. https://doi.org/10.1152/physiolgenomics.00133.2016.
Pellegrini, K. L., Gerlach, C. V., Craciun, F. L., Ramachandran, K., Bijol, V., Kissick, H. T., et al. (2016). Application of small RNA sequencing to identify microRNAs in acute kidney injury and fibrosis. Toxicology and Applied Pharmacology, 312, 42–52. https://doi.org/10.1016/j.taap.2015.12.002.
Pereira, P., Queiroz, J. A., Figueiras, A., & Sousa, F. (2017). Current progress on microRNAs-based therapeutics in neurodegenerative diseases. Wiley Interdisciplinary Reviews: RNA. https://doi.org/10.1002/wrna.1409.
Quinlan, S., Kenny, A., Medina, M., Engel, T., & Jimenez-Mateos, E. M. (2017). microRNAs in neurodegenerative diseases. International Review of Cell and Molecular Biology, 334, 309–343. https://doi.org/10.1016/bs.ircmb.2017.04.002.
Ramlackhansingh, A. F., Brooks, D. J., Greenwood, R. J., Bose, S. K., Turkheimer, F. E., Kinnunen, K. M., et al. (2011). Inflammation after trauma: Microglial activation and traumatic brain injury. Annals of Neurology, 70(3), 374–383. https://doi.org/10.1002/ana.22455.
Redell, J. B., Liu, Y., & Dash, P. K. (2009). Traumatic brain injury alters expression of hippocampal microRNAs: Potential regulators of multiple pathophysiological processes. Journal of Neuroscience Research, 87(6), 1435–1448. https://doi.org/10.1002/jnr.21945.
Redell, J. B., Moore, A. N., Ward, N. H., 3rd, Hergenroeder, G. W., & Dash, P. K. (2010). Human traumatic brain injury alters plasma microRNA levels. Journal of Neurotrauma, 27(12), 2147–2156. https://doi.org/10.1089/neu.2010.1481.
Schwulst, S. J., Trahanas, D. M., Saber, R., & Perlman, H. (2013). Traumatic brain injury-induced alterations in peripheral immunity. The Journal of Trauma and Acute Care Surgery, 75(5), 780–788. https://doi.org/10.1097/TA.0b013e318299616a.
Shah, S. Z. A., Zhao, D., Hussain, T., Sabir, N., & Yang, L. (2018). Regulation of microRNAs-mediated autophagic flux: A new regulatory avenue for neurodegenerative diseases with focus on prion diseases. Frontiers in Aging Neuroscience, 10, 139. https://doi.org/10.3389/fnagi.2018.00139.
Sheinerman, K. S., Toledo, J. B., Tsivinsky, V. G., Irwin, D., Grossman, M., Weintraub, D., et al. (2017). Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases. Alzheimer's Research & Therapy, 9(1), 89. https://doi.org/10.1186/s13195-017-0316-0.
Sun, P., Liu, D. Z., Jickling, G. C., Sharp, F. R., & Yin, K. J. (2018). microRNA-based therapeutics in central nervous system injuries. Journal of Cerebral Blood Flow and Metabolism, 38(7), 1125–1148. https://doi.org/10.1177/0271678X18773871.
Taganov, K. D., Boldin, M. P., Chang, K. J., & Baltimore, D. (2006). NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12481–12486. https://doi.org/10.1073/pnas.0605298103.
Tao, L., Li, D., Liu, H., Jiang, F., Xu, Y., Cao, Y., et al. (2018). Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-kappaB and MAPK signaling pathway. Brain Research Bulletin, 140, 154–161. https://doi.org/10.1016/j.brainresbull.2018.04.008.
Theus, M. H., Brickler, T., Meza, A. L., Coutermarsh-Ott, S., Hazy, A., Gris, D., et al. (2017). Loss of NLRX1 exacerbates neural tissue damage and NF-kappa B signaling following brain injury. The Journal of Immunology, 199(10), 3547–3558. https://doi.org/10.4049/jimmunol.1700251.
Thurman, D. J. (2016). The epidemiology of traumatic brain injury in children and youths: A review of research since 1990. Journal of Child Neurology, 31(1), 20–27. https://doi.org/10.1177/0883073814544363.
Xiong, Y., Mahmood, A., & Chopp, M. (2018). Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities. Chinese Journal of Traumatology, 21(3), 137–151. https://doi.org/10.1016/j.cjtee.2018.02.003.
Zhu, W., Zhao, L., Li, T., Xu, H., Ding, Y., & Cui, G. (2019). Docosahexaenoic acid ameliorates traumatic brain injury involving JNK-mediated Tau phosphorylation signaling. Neuroscience Research. https://doi.org/10.1016/j.neures.2019.07.008.
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Lei Zhang and Li Zhao have contributed equally to this paper, and should be regarded as co-first authors.
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Zhang, L., Zhao, L., Zhu, W. et al. miR-146a Mimics Ameliorates Traumatic Brain Injury Involving JNK and NF-κB Signaling Pathway. Neuromol Med 22, 484–492 (2020). https://doi.org/10.1007/s12017-020-08599-y
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DOI: https://doi.org/10.1007/s12017-020-08599-y