Overview of Traumatic Brain Injury: An Immunological Context

Damir Nizamutdinov, Lee A Shapiro, Damir Nizamutdinov, Lee A Shapiro

Abstract

Traumatic brain injury (TBI) afflicts people of all ages and genders, and the severity of injury ranges from concussion/mild TBI to severe TBI. Across all spectrums, TBI has wide-ranging, and variable symptomology and outcomes. Treatment options are lacking for the early neuropathology associated with TBIs and for the chronic neuropathological and neurobehavioral deficits. Inflammation and neuroinflammation appear to be major mediators of TBI outcomes. These systems are being intensively studies using animal models and human translational studies, in the hopes of understanding the mechanisms of TBI, and developing therapeutic strategies to improve the outcomes of the millions of people impacted by TBIs each year. This manuscript provides an overview of the epidemiology and outcomes of TBI, and presents data obtained from animal and human studies focusing on an inflammatory and immunological context. Such a context is timely, as recent studies blur the traditional understanding of an "immune-privileged" central nervous system. In presenting the evidence for specific, adaptive immune response after TBI, it is hoped that future studies will be interpreted using a broader perspective that includes the contributions of the peripheral immune system, to central nervous system disorders, notably TBI and post-traumatic syndromes.

Keywords: neuroimmunity; neuroinflammation; traumatic brain injury.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Marr A.L., Coronado V.G. Central Nervous System Injury Surveillance Data Submission Standards—2002. Department of Health and Human Services; Washington, DC, USA: 2004.
    1. Centers for Disease Control and Prevention (CDC) Traumatic Brain Injury in the United States: Fact Sheet. [(accessed on 15 September 2016)]; Available online: .
    1. Faul M.X., Xu L., Wald M.M., Coronad V.G. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. [(accessed on 15 September 2016)]; Available online: .
    1. Zaloshnja E., Miller T., Langlois J.A., Selassie A.W. Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. J. Head Trauma Rehabil. 2008;23:394–400. doi: 10.1097/.
    1. Centers for Disease Control and Prevention (CDC) United States Department of Defense (DOD) VA Leadership Panel Report to Congress on Traumatic Brain Injury in the United States: Understanding the Public Health Problem among Current and Former Military Personnel. [(accessed on 15 September 2016)]; Available online: .
    1. Teasdale G., Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2:81–84. doi: 10.1016/S0140-6736(74)91639-0.
    1. Jennett B., Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480–484. doi: 10.1016/S0140-6736(75)92830-5.
    1. Nakase-Richardson R., Sherer M., Seel R.T., Hart T., Hanks R., Arango-Lasprilla J.C., Yablon S.A., Sander A.M., Barnett S.D., Walker W.C., et al. Utility of post-traumatic amnesia in predicting 1-year productivity following traumatic brain injury: Comparison of the Russell and Mississippi PTA classification intervals. J. Neurol. Neurosurg. Psychiatry. 2011;82:494–499. doi: 10.1136/jnnp.2010.222489.
    1. Brenner L.A., Vanderploeg R.D., Terrio H. Assessment and diagnosis of mild traumatic brain injury, posttraumatic stress disorder, and other polytrauma conditions: Burden of adversity hypothesis. Rehabil. Psychol. 2009;54:239–246. doi: 10.1037/a0016908.
    1. Turan N., Miller B.A., Heider R.A., Nadeem M., Sayeed I., Stein D.G., Pradilla G. Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents. J. Cereb. Blood Flow Metab. 2016 doi: 10.1177/0271678X16665623.
    1. Riggio S., Wong M. Neurobehavioral sequelae of traumatic brain injury. Mt. Sinai J. Med. 2009;76:163–172. doi: 10.1002/msj.20097.
    1. Walker W.C., Pickett T.C. Motor impairment after severe traumatic brain injury: A longitudinal multicenter study. J. Rehabil. Res. Dev. 2007;44:975–982. doi: 10.1682/JRRD.2006.12.0158.
    1. Safaz I., Alaca R., Yasar E., Tok F., Yilmaz B. Medical complications, physical function and communication skills in patients with traumatic brain injury: A single centre 5-year experience. Brain Inj. 2008;22:733–739. doi: 10.1080/02699050802304714.
    1. Rosenthal M., Christensen B.K., Ross T.P. Depression following traumatic brain injury. Arch. Phys. Med. Rehabil. 1998;79:90–103. doi: 10.1016/S0003-9993(98)90215-5.
    1. Hart T., Brenner L., Clark A.N., Bogner J.A., Novack T.A., Chervoneva I., Nakase-Richardson R., Arango-Lasprilla J.C. Major and minor depression after traumatic brain injury. Arch. Phys. Med. Rehabil. 2011;92:1211–1219. doi: 10.1016/j.apmr.2011.03.005.
    1. Stulemeijer M., Vos P.E., Bleijenberg G., van der Werf S.P. Cognitive complaints after mild traumatic brain injury: Things are not always what they seem. J. Psychosom. Res. 2007;63:637–645. doi: 10.1016/j.jpsychores.2007.06.023.
    1. Agrawal A., Timothy J., Pandit L., Manju M. Post-traumatic epilepsy: An overview. Clin. Neurol. Neurosurg. 2006;108:433–439. doi: 10.1016/j.clineuro.2005.09.001.
    1. Bazarian J.J., Cernak I., Noble-Haeusslein L., Potolicchio S., Temkin N. Long-term neurologic outcomes after traumatic brain injury. J. Head Trauma Rehabil. 2009;24:439–451. doi: 10.1097/HTR.0b013e3181c15600.
    1. Carbonell W.S., Maris D.O., McCall T., Grady M.S. Adaptation of the fluid percussion injury model to the mouse. J. Neurotrauma. 1998;15:217–229. doi: 10.1089/neu.1998.15.217.
    1. Dixon C.E., Lighthall J.W., Anderson T.E. Physiologic, histopathologic, and cineradiographic characterization of a new fluid-percussion model of experimental brain injury in the rat. J. Neurotrauma. 1988;5:91–104. doi: 10.1089/neu.1988.5.91.
    1. Dixon C.E., Lyeth B.G., Povlishock J.T., Findling R.L., Hamm R.J., Marmarou A., Young H.F., Hayes R.L. A fluid percussion model of experimental brain injury in the rat. J. Neurosurg. 1987;67:110–119. doi: 10.3171/jns.1987.67.1.0110.
    1. Mukherjee S., Zeitouni S., Cavarsan C.F., Shapiro L.A. Increased seizure susceptibility in mice 30 days after fluid percussion injury. Front. Neurol. 2013;4:28. doi: 10.3389/fneur.2013.00028.
    1. Dixon C.E., Clifton G.L., Lighthall J.W., Yaghmai A.A., Hayes R.L. A controlled cortical impact model of traumatic brain injury in the rat. J. Neurosci. Methods. 1991;39:253–262. doi: 10.1016/0165-0270(91)90104-8.
    1. Lighthall J.W. Controlled cortical impact: A new experimental brain injury model. J. Neurotrauma. 1988;5:1–15. doi: 10.1089/neu.1988.5.1.
    1. Smith D.H., Soares H.D., Pierce J.S., Perlman K.G., Saatman K.E., Meaney D.F., Dixon C.E., McIntosh T.K. A model of parasagittal controlled cortical impact in the mouse: Cognitive and histopathologic effects. J. Neurotrauma. 1995;12:169–178. doi: 10.1089/neu.1995.12.169.
    1. Williams A.J., Hartings J.A., Lu X.C., Rolli M.L., Dave J.R., Tortella F.C. Characterization of a new rat model of penetrating ballistic brain injury. J. Neurotrauma. 2005;22:313–331. doi: 10.1089/neu.2005.22.313.
    1. Marmarou A., Foda M.A., van den Brink W., Campbell J., Kita H., Demetriadou K. A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J. Neurosurg. 1994;80:291–300. doi: 10.3171/jns.1994.80.2.0291.
    1. Cernak I., Savic J., Malicevic Z., Zunic G., Radosevic P., Ivanovic I., Davidovic L. Involvement of the central nervous system in the general response to pulmonary blast injury. J. Trauma. 1996;40:S100–S104. doi: 10.1097/00005373-199603001-00023.
    1. Warden D. Military tbi during the iraq and afghanistan wars. J. Head Trauma Rehabil. 2006;21:398–402. doi: 10.1097/00001199-200609000-00004.
    1. McIntosh T.K., Noble L., Andrews B., Faden A.I. Traumatic brain injury in the rat: Characterization of a midline fluid-percussion model. Cent. Nerv. Syst. Trauma. 1987;4:119–134. doi: 10.1089/cns.1987.4.119.
    1. McIntosh T.K., Vink R., Noble L., Yamakami I., Fernyak S., Soares H., Faden A.L. Traumatic brain injury in the rat: Characterization of a lateral fluid-percussion model. Neuroscience. 1989;28:233–244. doi: 10.1016/0306-4522(89)90247-9.
    1. Kabadi S.V., Hilton G.D., Stoica B.A., Zapple D.N., Faden A.I. Fluid-percussion-induced traumatic brain injury model in rats. Nat. Protoc. 2010;5:1552–1563. doi: 10.1038/nprot.2010.112.
    1. Walter B., Bauer R., Fritz H., Jochum T., Wunder L., Zwiener U. Evaluation of micro tip pressure transducers for the measurement of intracerebral pressure transients induced by fluid percussion. Exp. Toxicol. Pathol. 1999;51:124–129. doi: 10.1016/S0940-2993(99)80085-2.
    1. Alder J., Fujioka W., Lifshitz J., Crockett D.P., Thakker-Varia S. Lateral fluid percussion: Model of traumatic brain injury in mice. J. Vis. Exp. 2011;54:e3063. doi: 10.3791/3063.
    1. Thompson H.J., Lifshitz J., Marklund N., Grady M.S., Graham D.I., Hovda D.A., McIntosh T.K. Lateral fluid percussion brain injury: A 15-year review and evaluation. J. Neurotrauma. 2005;22:42–75. doi: 10.1089/neu.2005.22.42.
    1. Morales D.M., Marklund N., Lebold D., Thompson H.J., Pitkanen A., Maxwell W.L., Longhi L., Laurer H., Maegele M., Neugebauer E., et al. Experimental models of traumatic brain injury: Do we really need to build a better mousetrap? Neuroscience. 2005;136:971–989. doi: 10.1016/j.neuroscience.2005.08.030.
    1. Hartl R., Medary M., Ruge M., Arfors K.E., Ghajar J. Blood-brain barrier breakdown occurs early after traumatic brain injury and is not related to white blood cell adherence. Acta Neurochir. Suppl. 1997;70:240–242.
    1. Das M., Leonardo C.C., Rangooni S., Pennypacker K.R., Mohapatra S., Mohapatra S.S. Lateral fluid percussion injury of the brain induces CCL20 inflammatory chemokine expression in rats. J. Neuroinflamm. 2011;8:148. doi: 10.1186/1742-2094-8-148.
    1. Xiong Y., Mahmood A., Chopp M. Animal models of traumatic brain injury. Nat. Rev. Neurosci. 2013;14:128–142. doi: 10.1038/nrn3407.
    1. Graham D.I., McIntosh T.K., Maxwell W.L., Nicoll J.A. Recent advances in neurotrauma. J. Neuropathol. Exp. Neurol. 2000;59:641–651. doi: 10.1093/jnen/59.8.641.
    1. Sanders M.J., Dietrich W.D., Green E.J. Cognitive function following traumatic brain injury: Effects of injury severity and recovery period in a parasagittal fluid-percussive injury model. J. Neurotrauma. 1999;16:915–925. doi: 10.1089/neu.1999.16.915.
    1. Vink R., Mullins P.G., Temple M.D., Bao W., Faden A.I. Small shifts in craniotomy position in the lateral fluid percussion injury model are associated with differential lesion development. J. Neurotrauma. 2001;18:839–847. doi: 10.1089/089771501316919201.
    1. Floyd C.L., Golden K.M., Black R.T., Hamm R.J., Lyeth B.G. Craniectomy position affects morris water maze performance and hippocampal cell loss after parasagittal fluid percussion. J. Neurotrauma. 2002;19:303–316. doi: 10.1089/089771502753594873.
    1. Hayes R.L., Stalhammar D., Povlishock J.T., Allen A.M., Galinat B.J., Becker D.P., Stonnington H.H. A new model of concussive brain injury in the cat produced by extradural fluid volume loading: II. Physiological and neuropathological observations. Brain Inj. 1987;1:93–112. doi: 10.3109/02699058709034449.
    1. Millen J.E., Glauser F.L., Fairman R.P. A comparison of physiological responses to percussive brain trauma in dogs and sheep. J. Neurosurg. 1985;62:587–591. doi: 10.3171/jns.1985.62.4.0587.
    1. Pfenninger E.G., Reith A., Breitig D., Grunert A., Ahnefeld F.W. Early changes of intracranial pressure, perfusion pressure, and blood flow after acute head injury. Part 1: An experimental study of the underlying pathophysiology. J. Neurosurg. 1989;70:774–779. doi: 10.3171/jns.1989.70.5.0774.
    1. Hicks R., Soares H., Smith D., McIntosh T. Temporal and spatial characterization of neuronal injury following lateral fluid-percussion brain injury in the rat. Acta Neuropathol. 1996;91:236–246. doi: 10.1007/s004010050421.
    1. Liu Y.R., Cardamone L., Hogan R.E., Gregoire M.C., Williams J.P., Hicks R.J., Binns D., Koe A., Jones N.C., Myers D.E., et al. Progressive metabolic and structural cerebral perturbations after traumatic brain injury: An in vivo imaging study in the rat. J. Nucl. Med. 2010;51:1788–1795. doi: 10.2967/jnumed.110.078626.
    1. Hamm R.J. Neurobehavioral assessment of outcome following traumatic brain injury in rats: An evaluation of selected measures. J. Neurotrauma. 2001;18:1207–1216. doi: 10.1089/089771501317095241.
    1. Pierce J.E., Smith D.H., Trojanowski J.Q., McIntosh T.K. Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats. Neuroscience. 1998;87:359–369. doi: 10.1016/S0306-4522(98)00142-0.
    1. King C., Robinson T., Dixon C.E., Rao G.R., Larnard D., Nemoto C.E. Brain temperature profiles during epidural cooling with the chillerpad in a monkey model of traumatic brain injury. J. Neurotrauma. 2010;27:1895–1903. doi: 10.1089/neu.2009.1178.
    1. Acosta S.A., Tajiri N., Shinozuka K., Ishikawa H., Grimmig B., Diamond D.M., Sanberg P.R., Bickford P.C., Kaneko Y., Borlongan C.V. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS ONE. 2013;8:e53376. doi: 10.1371/annotation/a04a7468-d105-42f3-ba47-263ea2864681.
    1. Hall E.D., Sullivan P.G., Gibson T.R., Pavel K.M., Thompson B.M., Scheff S.W. Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: More than a focal brain injury. J. Neurotrauma. 2005;22:252–265. doi: 10.1089/neu.2005.22.252.
    1. Goodman J.C., Cherian L., Bryan R.M., Jr., Robertson C.S. Lateral cortical impact injury in rats: Pathologic effects of varying cortical compression and impact velocity. J. Neurotrauma. 1994;11:587–597. doi: 10.1089/neu.1994.11.587.
    1. Saatman K.E., Feeko K.J., Pape R.L., Raghupathi R. Differential behavioral and histopathological responses to graded cortical impact injury in mice. J. Neurotrauma. 2006;23:1241–1253. doi: 10.1089/neu.2006.23.1241.
    1. Petraglia A.L., Plog B.A., Dayawansa S., Chen M., Dashnaw M.L., Czerniecka K., Walker C.T., Viterise T., Hyrien O., Iliff J.J., et al. The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: A novel mouse model of chronic traumatic encephalopathy. J. Neurotrauma. 2014;31:1211–1224. doi: 10.1089/neu.2013.3255.
    1. Fox G.B., Fan L., Levasseur R.A., Faden A.I. Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J. Neurotrauma. 1998;15:599–614. doi: 10.1089/neu.1998.15.599.
    1. Washington P.M., Forcelli P.A., Wilkins T., Zapple D.N., Parsadanian M., Burns M.P. The effect of injury severity on behavior: A phenotypic study of cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact injury in mice. J. Neurotrauma. 2012;29:2283–2296. doi: 10.1089/neu.2012.2456.
    1. Marklund N., Hillered L. Animal modelling of traumatic brain injury in preclinical drug development: Where do we go from here? Br. J. Pharmacol. 2011;164:1207–1229. doi: 10.1111/j.1476-5381.2010.01163.x.
    1. Dixon C.E., Kraus M.F., Kline A.E., Ma X., Yan H.Q., Griffith R.G., Wolfson B.M., Marion D.W. Amantadine improves water maze performance without affecting motor behavior following traumatic brain injury in rats. Restor. Neurol. Neurosci. 1999;14:285–294.
    1. Dixon C.E., Kochanek P.M., Yan H.Q., Schiding J.K., Griffith R.G., Baum E., Marion D.W., DeKosky S.T. One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats. J. Neurotrauma. 1999;16:109–122. doi: 10.1089/neu.1999.16.109.
    1. Masel B.E., DeWitt D.S. Traumatic brain injury: A disease process, not an event. J. Neurotrauma. 2010;27:1529–1540. doi: 10.1089/neu.2010.1358.
    1. Davis A.E. Mechanisms of traumatic brain injury: Biomechanical, structural and cellular considerations. Crit. Care Nurs. Q. 2000;23:1–13. doi: 10.1097/00002727-200011000-00002.
    1. Gaetz M. The neurophysiology of brain injury. Clin. Neurophysiol. 2004;115:4–18. doi: 10.1016/S1388-2457(03)00258-X.
    1. Cernak I. Animal models of head trauma. NeuroRx. 2005;2:410–422. doi: 10.1602/neurorx.2.3.410.
    1. Bramlett H.M., Dietrich W.D. Progressive damage after brain and spinal cord injury: Pathomechanisms and treatment strategies. Prog. Brain Res. 2007;161:125–141.
    1. Marklund N., Bakshi A., Castelbuono D.J., Conte V., McIntosh T.K. Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr. Pharm. Des. 2006;12:1645–1680. doi: 10.2174/138161206776843340.
    1. Povlishock J.T., Christman C.W. The pathobiology of traumatically induced axonal injury in animals and humans: A review of current thoughts. J. Neurotrauma. 1995;12:555–564. doi: 10.1089/neu.1995.12.555.
    1. Arvin B., Neville L.F., Barone F.C., Feuerstein G.Z. Brain injury and inflammation. A putative role of TNF alpha. Ann. N. Y. Acad. Sci. 1995;765:62–71. doi: 10.1111/j.1749-6632.1995.tb16561.x.
    1. Isaksson J., Lewen A., Hillered L., Olsson Y. Up-regulation of intercellular adhesion molecule 1 in cerebral microvessels after cortical contusion trauma in a rat model. Acta Neuropathol. 1997;94:16–20. doi: 10.1007/s004010050666.
    1. Yang K., Mu X.S., Xue J.J., Whitson J., Salminen A., dixon C.E., Liu P.K., Hayes R.L. Increased expression of c-fos mRNA and AP-1 transcription factors after cortical impact injury in rats. Brain Res. 1994;664:141–147. doi: 10.1016/0006-8993(94)91964-X.
    1. Yatsiv I., Morganti-Kossmann M.C., Perez D., Dinarello C.A., Novick D., Rubinstein M., Otto V.I., Rancan M., Kossmann T., Redaelli C.A., et al. Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury. J. Cereb. Blood Flow Metab. 2002;22:971–978. doi: 10.1097/00004647-200208000-00008.
    1. Hutchinson P.J., O’Connell M.T., Rothwell N.J., Hopkins S.J., Nortje J., Carpenter K.L., Timofeev I., Al-Rawi P.G., Menon D.K., Pickard J.D. Inflammation in human brain injury: Intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J. Neurotrauma. 2007;24:1545–1557. doi: 10.1089/neu.2007.0295.
    1. Utagawa A., Truettner J.S., Dietrich W.D., Bramlett H.M. Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats. Exp. Neurol. 2008;211:283–291. doi: 10.1016/j.expneurol.2008.02.001.
    1. Minami M., Kuraishi Y., Satoh M. Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and lif in the rat brain. Biochem. Biophys. Res. Commun. 1991;176:593–598. doi: 10.1016/S0006-291X(05)80225-6.
    1. Liu T., Clark R.K., McDonnell P.C., Young P.R., White R.F., Barone F.C., Feuerstein G.Z. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke. 1994;25:1481–1488. doi: 10.1161/01.STR.25.7.1481.
    1. Chizzolini C., Dayer J.M., Miossec P. Cytokines in chronic rheumatic diseases: Is everything lack of homeostatic balance? Arthritis Res. Ther. 2009;11:246. doi: 10.1186/ar2767.
    1. Iwasaki A., Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327:291–295. doi: 10.1126/science.1183021.
    1. Zhang J.M., An J. Cytokines, inflammation, and pain. Int. Anesthesiol. Clin. 2007;45:27–37. doi: 10.1097/AIA.0b013e318034194e.
    1. Dinarello C.A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 2009;27:519–550. doi: 10.1146/annurev.immunol.021908.132612.
    1. Garlanda C., Dinarello C.A., Mantovani A. The interleukin-1 family: Back to the future. Immunity. 2013;39:1003–1018. doi: 10.1016/j.immuni.2013.11.010.
    1. Pearson V.L., Rothwell N.J., Toulmond S. Excitotoxic brain damage in the rat induces interleukin-1beta protein in microglia and astrocytes: Correlation with the progression of cell death. Glia. 1999;25:311–323. doi: 10.1002/(SICI)1098-1136(19990215)25:4<311::AID-GLIA1>;2-E.
    1. Dinarello C.A. Blocking IL-1 in systemic inflammation. J. Exp. Med. 2005;201:1355–1359. doi: 10.1084/jem.20050640.
    1. Dinarello C.A. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am. J. Clin. Nutr. 2006;83:447S–455S.
    1. Lu K.T., Wang Y.W., Wo Y.Y., Yang Y.L. Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury. Neurosci. Lett. 2005;386:40–45. doi: 10.1016/j.neulet.2005.05.057.
    1. Liu T., Young P.R., McDonnell P.C., White R.F., Barone F.C., Feuerstein G.Z. Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia. Neurosci. Lett. 1993;164:125–128. doi: 10.1016/0304-3940(93)90873-J.
    1. Grilli M., Memo M. Nuclear factor-kappaB/Rel proteins: A point of convergence of signalling pathways relevant in neuronal function and dysfunction. Biochem. Pharmacol. 1999;57:1–7. doi: 10.1016/S0006-2952(98)00214-7.
    1. Baeuerle P.A., Baltimore D. NF-kappa B: Ten years after. Cell. 1996;87:13–20. doi: 10.1016/S0092-8674(00)81318-5.
    1. Jander S., Stoll G. Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the lewis rat. J. Neuroimmunol. 1998;91:93–99. doi: 10.1016/S0165-5728(98)00162-3.
    1. Losy J., Niezgoda A. IL-18 in patients with multiple sclerosis. Acta Neurol. Scand. 2001;104:171–173. doi: 10.1034/j.1600-0404.2001.00356.x.
    1. Fassbender K., Mielke O., Bertsch T., Muehlhauser F., Hennerici M., Kurimoto M., Rossol S. Interferon-gamma-inducing factor (IL-18) and interferon-gamma in inflammatory CNS diseases. Neurology. 1999;53:1104–1106. doi: 10.1212/WNL.53.5.1104.
    1. Sims J.E., Smith D.E. The IL-1 family: Regulators of immunity. Nat. Rev. Immunol. 2010;10:89–102. doi: 10.1038/nri2691.
    1. Kremlev S.G., Roberts R.L., Palmer C. Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. J. Neuroimmunol. 2004;149:1–9. doi: 10.1016/j.jneuroim.2003.11.012.
    1. Gyoneva S., Ransohoff R.M. Inflammatory reaction after traumatic brain injury: Therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol. Sci. 2015;36:471–480. doi: 10.1016/j.tips.2015.04.003.
    1. Choi S.S., Lee H.J., Lim I., Satoh J., Kim S.U. Human astrocytes: Secretome profiles of cytokines and chemokines. PLoS ONE. 2014;9:e92325. doi: 10.1371/journal.pone.0092325.
    1. Ono S.J., Nakamura T., Miyazaki D., Ohbayashi M., Dawson M., Toda M. Chemokines: Roles in leukocyte development, trafficking, and effector function. J. Allergy Clin. Immunol. 2003;111:1185–1199. doi: 10.1067/mai.2003.1594.
    1. Helmy A., Carpenter K.L., Menon D.K., Pickard J.D., Hutchinson P.J. The cytokine response to human traumatic brain injury: Temporal profiles and evidence for cerebral parenchymal production. J. Cereb. Blood Flow Metab. 2011;31:658–670. doi: 10.1038/jcbfm.2010.142.
    1. Helmy A., Antoniades C.A., Guilfoyle M.R., Carpenter K.L., Hutchinson P.J. Principal component analysis of the cytokine and chemokine response to human traumatic brain injury. PLoS ONE. 2012;7:e39677. doi: 10.1371/journal.pone.0039677.
    1. Glabinski A.R., Tani M., Aras S., Stoler M.H., Tuohy V.K., Ransohoff R.M. Regulation and function of central nervous system chemokines. Int. J. Dev. Neurosci. 1995;13:153–165. doi: 10.1016/0736-5748(95)00017-B.
    1. Ghirnikar R.S., Lee Y.L., Eng L.F. Inflammation in traumatic brain injury: Role of cytokines and chemokines. Neurochem. Res. 1998;23:329–340. doi: 10.1023/A:1022453332560.
    1. Cartier L., Hartley O., Dubois-Dauphin M., Krause K.H. Chemokine receptors in the central nervous system: Role in brain inflammation and neurodegenerative diseases. Brain Res. Brain Res. Rev. 2005;48:16–42. doi: 10.1016/j.brainresrev.2004.07.021.
    1. Proudfoot A.E., Handel T.M., Johnson Z., Lau E.K., LiWang P., Clark-Lewis I., Borlat F., Wells T.N., Kosco-Vilbois M.H. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc. Natl. Acad. Sci. USA. 2003;100:1885–1890. doi: 10.1073/pnas.0334864100.
    1. Mantovani A., Sica A., Sozzani S., Allavena P., Vecchi A., Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–686. doi: 10.1016/j.it.2004.09.015.
    1. Shi C., Pamer E.G. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 2011;11:762–774. doi: 10.1038/nri3070.
    1. Tang D., Kang R., Coyne C.B., Zeh H.J., Lotze M.T. PAMPs and DAMPs: Signal 0s that spur autophagy and immunity. Immunol. Rev. 2012;249:158–175. doi: 10.1111/j.1600-065X.2012.01146.x.
    1. Sansonetti P.J. The innate signaling of dangers and the dangers of innate signaling. Nat. Immunol. 2006;7:1237–1242. doi: 10.1038/ni1420.
    1. Trinchieri G., Sher A. Cooperation of toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 2007;7:179–190. doi: 10.1038/nri2038.
    1. Ting J.P., Lovering R.C., Alnemri E.S., Bertin J., Boss J.M., Davis B.K., Flavell R.A., Girardin S.E., Godzik A., Harton J.A., et al. The NLR gene family: A standard nomenclature. Immunity. 2008;28:285–287. doi: 10.1016/j.immuni.2008.02.005.
    1. Strober W., Murray P.J., Kitani A., Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat. Rev. Immunol. 2006;6:9–20. doi: 10.1038/nri1747.
    1. Liu H.D., Li W., Chen Z.R., Hu Y.C., Zhang D.D., Shen W., Zhou M.L., Zhu L., Hang C.H. Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem. Res. 2013;38:2072–2083. doi: 10.1007/s11064-013-1115-z.
    1. Needham E., Zandi M.S. Recent advances in the neuroimmunology of cell-surface CNS autoantibody syndromes, Alzheimer’s disease, traumatic brain injury and schizophrenia. J. Neurol. 2014;261:2037–2042. doi: 10.1007/s00415-014-7473-x.
    1. Martinon F., Burns K., Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proil-beta. Mol. Cell. 2002;10:417–426. doi: 10.1016/S1097-2765(02)00599-3.
    1. Halle A., Hornung V., Petzold G.C., Stewart C.R., Monks B.G., Reinheckel T., Fitzgerald K.A., Latz E., Moore K.J., Golenbock D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 2008;9:857–865. doi: 10.1038/ni.1636.
    1. Trahanas D.M., Cuda C.M., Perlman H., Schwulst S.J. Differential activation of infiltrating monocyte-derived cells after mild and severe traumatic brain injury. Shock. 2015;43:255–260. doi: 10.1097/SHK.0000000000000291.
    1. Rhodes J. Peripheral immune cells in the pathology of traumatic brain injury? Curr. Opin. Crit. Care. 2011;17:122–130. doi: 10.1097/MCC.0b013e3283447948.
    1. Tobin R.P., Mukherjee S., Kain J.M., Rogers S.K., Henderson S.K., Motal H.L., Newell Rogers M.K., Shapiro L.A. Traumatic brain injury causes selective, CD74-dependent peripheral lymphocyte activation that exacerbates neurodegeneration. Acta Neuropathol. Commun. 2014;2:143. doi: 10.1186/s40478-014-0143-5.
    1. Schwulst S.J., Trahanas D.M., Saber R., Perlman H. Traumatic brain injury-induced alterations in peripheral immunity. J. Trauma Acute Care Surg. 2013;75:780–788. doi: 10.1097/TA.0b013e318299616a.
    1. Rasouli J., Lekhraj R., Ozbalik M., Lalezari P., Casper D. Brain-spleen inflammatory coupling: A literature review. Einstein J. Biol. Med. 2011;27:74–77. doi: 10.23861/EJBM20112768.
    1. Schwartz M., Deczkowska A. Neurological disease as a failure of brain-immune crosstalk: The multiple faces of neuroinflammation. Trends Immunol. 2016;37:668–679. doi: 10.1016/j.it.2016.08.001.
    1. Schwartz M. Helping the body to cure itself: Immune modulation by therapeutic vaccination for spinal cord injury. J. Spinal Cord Med. 2003;26:S6–S10. doi: 10.1080/10790268.2003.11753719.
    1. Foley L.M., Hitchens T.K., Ho C., Janesko-Feldman K.L., Melick J.A., Bayir H., Kochanek P.M. Magnetic resonance imaging assessment of macrophage accumulation in mouse brain after experimental traumatic brain injury. J. Neurotrauma. 2009;26:1509–1519. doi: 10.1089/neu.2008.0747.
    1. Soares H.D., Hicks R.R., Smith D., McIntosh T.K. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J. Neurosci. 1995;15:8223–8233.
    1. Kenne E., Erlandsson A., Lindbom L., Hillered L., Clausen F. Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice. J. Neuroinflamm. 2012;9:17. doi: 10.1186/1742-2094-9-17.
    1. Clark R.S., Schiding J.K., Kaczorowski S.L., Marion D.W., Kochanek P.M. Neutrophil accumulation after traumatic brain injury in rats: Comparison of weight drop and controlled cortical impact models. J. Neurotrauma. 1994;11:499–506. doi: 10.1089/neu.1994.11.499.
    1. Harlan J.M. Leukocyte-endothelial interactions. Blood. 1985;65:513–525.
    1. Kochanek P.M., Hallenbeck J.M. Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke. 1992;23:1367–1379. doi: 10.1161/01.STR.23.9.1367.
    1. Lucchesi B.R., Mullane K.M. Leukocytes and ischemia-induced myocardial injury. Annu. Rev. Pharmacol. Toxicol. 1986;26:201–224. doi: 10.1146/annurev.pa.26.040186.001221.
    1. Burke-Gaffney A., Keenan A.K. Modulation of human endothelial cell permeability by combinations of the cytokines interleukin-1 alpha/beta, tumor necrosis factor-alpha and interferon-gamma. Immunopharmacology. 1993;25:1–9. doi: 10.1016/0162-3109(93)90025-L.
    1. Clark W.M., Madden K.P., Rothlein R., Zivin J.A. Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment. Stroke. 1991;22:877–883. doi: 10.1161/01.STR.22.7.877.
    1. Schwartz M., Yoles E. Macrophages and dendritic cells treatment of spinal cord injury: From the bench to the clinic. Acta Neurochir. Suppl. 2005;93:147–150.
    1. Zindler E., Zipp F. Neuronal injury in chronic CNS inflammation. Best Pract. Res. Clin. Anaesthesiol. 2010;24:551–562. doi: 10.1016/j.bpa.2010.11.001.
    1. Herz J., Zipp F., Siffrin V. Neurodegeneration in autoimmune CNS inflammation. Exp. Neurol. 2010;225:9–17. doi: 10.1016/j.expneurol.2009.11.019.
    1. Jin X., Ishii H., Bai Z., Itokazu T., Yamashita T. Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS ONE. 2012;7:e41892. doi: 10.1371/journal.pone.0041892.
    1. Hu X., Li P., Guo Y., Wang H., Leak R.K., Chen S., Gao Y., Chen J. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43:3063–3070. doi: 10.1161/STROKEAHA.112.659656.
    1. Rolls A., Shechter R., London A., Segev Y., Jacob-Hirsch J., Amariglio N., Rechavi G., Schwartz M. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: A role in microglia/macrophage activation. PLoS Med. 2008;5:e171. doi: 10.1371/journal.pmed.0050171.
    1. Heppner F.L., Ransohoff R.M., Becher B. Immune attack: The role of inflammation in alzheimer disease. Nat. Rev. Neurosci. 2015;16:358–372. doi: 10.1038/nrn3880.
    1. Martinez F.O., Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 2014;6:13. doi: 10.12703/P6-13.
    1. Verma S., Nakaoke R., Dohgu S., Banks W.A. Release of cytokines by brain endothelial cells: A polarized response to lipopolysaccharide. Brain Behav. Immun. 2006;20:449–455. doi: 10.1016/j.bbi.2005.10.005.
    1. Jang E., Lee S., Kim J.H., Kim J.H., Seo J.W., Lee W.H., Mori K., Nakao K., Suk K. Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J. 2013;27:1176–1190. doi: 10.1096/fj.12-222257.
    1. Starossom S.C., Mascanfroni I.D., Imitola J., Cao L., Raddassi K., Hernandez S.F., Bassil R., Croci D.O., Cerliani J.P., Delacour D., et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012;37:249–263. doi: 10.1016/j.immuni.2012.05.023.
    1. Rocher C., Singla D.K. SMAD-PI3K-Akt-mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages. PLoS ONE. 2013;8:e84009. doi: 10.1371/journal.pone.0084009.
    1. Biswas S.K., Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat. Immunol. 2010;11:889–896. doi: 10.1038/ni.1937.
    1. Roughton K., Andreasson U., Blomgren K., Kalm M. Lipopolysaccharide-induced inflammation aggravates irradiation-induced injury to the young mouse brain. Dev. Neurosci. 2013;35:406–415. doi: 10.1159/000353820.
    1. Mukherjee S., Katki K., Arisi G.M., Foresti M.L., Shapiro L.A. Early tbi-induced cytokine alterations are similarly detected by two distinct methods of multiplex assay. Front. Mol. Neurosci. 2011;4:21. doi: 10.3389/fnmol.2011.00021.
    1. Ni K., O’Neill H.C. The role of dendritic cells in T cell activation. Immunol. Cell Biol. 1997;75:223–230. doi: 10.1038/icb.1997.35.
    1. Pozzi L.A., Maciaszek J.W., Rock K.L. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J. Immunol. 2005;175:2071–2081. doi: 10.4049/jimmunol.175.4.2071.
    1. Kelso M.L., Gendelman H.E. Bridge between neuroimmunity and traumatic brain injury. Curr. Pharm. Des. 2014;20:4284–4298. doi: 10.2174/13816128113196660653.
    1. Gyoneva S., Kim D., Katsumoto A., Kokiko-Cochran O.N., Lamb B.T., Ransohoff R.M. Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury. J. Neuroinflamm. 2015;12:228. doi: 10.1186/s12974-015-0443-0.
    1. Gelderblom M., Arunachalam P., Magnus T. Gammadelta T cells as early sensors of tissue damage and mediators of secondary neurodegeneration. Front. Cell Neurosci. 2014;8:368. doi: 10.3389/fncel.2014.00368.
    1. Sobottka B., Harrer M.D., Ziegler U., Fischer K., Wiendl H., Hunig T., Becher B., Goebels N. Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss. Am. J. Pathol. 2009;175:1160–1166. doi: 10.2353/ajpath.2009.090340.
    1. Melzer N., Meuth S.G., Wiendl H. CD8+ T cells and neuronal damage: Direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. FASEB J. 2009;23:3659–3673. doi: 10.1096/fj.09-136200.
    1. Serpe C.J., Coers S., Sanders V.M., Jones K.J. CD4+ T, but not CD8+ or B, lymphocytes mediate facial motoneuron survival after facial nerve transection. Brain Behav. Immun. 2003;17:393–402. doi: 10.1016/S0889-1591(03)00028-X.
    1. Schwartz M., Shechter R. Systemic inflammatory cells fight off neurodegenerative disease. Nat. Rev. Neurol. 2010;6:405–410. doi: 10.1038/nrneurol.2010.71.
    1. Cohen I.R. The cognitive paradigm and the immunological homunculus. Immunol. Today. 1992;13:490–494. doi: 10.1016/0167-5699(92)90024-2.
    1. Moalem G., Leibowitz-Amit R., Yoles E., Mor F., Cohen I.R., Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 1999;5:49–55.
    1. Bradl M., Bauer J., Flugel A., Wekerle H., Lassmann H. Complementary contribution of CD4 and CD8 T lymphocytes to T-cell infiltration of the intact and the degenerative spinal cord. Am. J. Pathol. 2005;166:1441–1450. doi: 10.1016/S0002-9440(10)62361-9.
    1. Burns J., Rosenzweig A., Zweiman B., Lisak R.P. Isolation of myelin basic protein-reactive T-cell lines from normal human blood. Cell. Immunol. 1983;81:435–440. doi: 10.1016/0008-8749(83)90250-2.
    1. Martin R., Jaraquemada D., Flerlage M., Richert J., Whitaker J., Long E.O., McFarlin D.E., McFarland H.F. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J. Immunol. 1990;145:540–548.
    1. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 2005;6:345–352. doi: 10.1038/ni1178.
    1. Fontenot J.D., Gavin M.A., Rudensky A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 2003;4:330–336. doi: 10.1038/ni904.
    1. Ben Simon G.J., Hovda D.A., Harris N.G., Gomez-Pinilla F., Goldberg R.A. Traumatic brain injury induced neuroprotection of retinal ganglion cells to optic nerve crush. J. Neurotrauma. 2006;23:1072–1082. doi: 10.1089/neu.2006.23.1072.
    1. Fisher J., Levkovitch-Verbin H., Schori H., Yoles E., Butovsky O., Kaye J.F., Ben-Nun A., Schwartz M. Vaccination for neuroprotection in the mouse optic nerve: Implications for optic neuropathies. J. Neurosci. 2001;21:136–142.
    1. Hazeldine J., Lord J.M., Belli A. Traumatic brain injury and peripheral immune suppression: Primer and prospectus. Front. Neurol. 2015;6:235. doi: 10.3389/fneur.2015.00235.
    1. Jesse S., Steinacker P., Cepek L., von Arnim C.A., Tumani H., Lehnert S., Kretzschmar H.A., Baier M., Otto M. Glial fibrillary acidic protein and protein s-100b: Different concentration pattern of glial proteins in cerebrospinal fluid of patients with alzheimer's disease and creutzfeldt-jakob disease. J. Alzheimers Dis. 2009;17:541–551. doi: 10.1016/j.jalz.2009.04.623.
    1. Posti J.P., Takala R.S., Runtti H., Newcombe V.F., Outtrim J., Katila A.J., Frantzen J., Ala-Seppala H., Coles J.P., Hossain M.I., et al. The levels of glial fibrillary acidic protein and ubiquitin c-terminal hydrolase-l1 during the first week after a traumatic brain injury: Correlations with clinical and imaging findings. Neurosurgery. 2016;79:456–464.
    1. Mondello S., Kobeissy F., Vestri A., Hayes R.L., Kochanek P.M., Berger R.P. Serum concentrations of ubiquitin c-terminal hydrolase-l1 and glial fibrillary acidic protein after pediatric traumatic brain injury. Sci. Rep. 2016;6:28203. doi: 10.1038/srep28203.
    1. Yan E.B., Satgunaseelan L., Paul E., Bye N., Nguyen P., Agyapomaa D., Kossmann T., Rosenfeld J.V., Morganti-Kossmann M.C. Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury. J. Neurotrauma. 2014;31:618–629. doi: 10.1089/neu.2013.3087.
    1. Ottens A.K., Golden E.C., Bustamante L., Hayes R.L., Denslow N.D., Wang K.K. Proteolysis of multiple myelin basic protein isoforms after neurotrauma: Characterization by mass spectrometry. J. Neurochem. 2008;104:1401–1414. doi: 10.1111/j.1471-4159.2007.05086.x.
    1. Cox A.L., Coles A.J., Nortje J., Bradley P.G., Chatfield D.A., Thompson S.J., Menon D.K. An investigation of auto-reactivity after head injury. J. Neuroimmunol. 2006;174:180–186. doi: 10.1016/j.jneuroim.2006.01.007.
    1. Kalia V., Sarkar S., Ahmed R. Cd8 t-cell memory differentiation during acute and chronic viral infections. Adv. Exp. Med. Biol. 2010;684:79–95.
    1. Goverman J. Autoimmune t cell responses in the central nervous system. Nat. Rev. Immunol. 2009;9:393–407. doi: 10.1038/nri2550.
    1. McFarland H.F., Martin R. Multiple sclerosis: A complicated picture of autoimmunity. Nat. Immunol. 2007;8:913–919. doi: 10.1038/ni1507.
    1. Lucchinetti C., Bruck W., Parisi J., Scheithauer B., Rodriguez M., Lassmann H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol. 2000;47:707–717. doi: 10.1002/1531-8249(200006)47:6<707::AID-ANA3>;2-Q.
    1. Ransohoff R.M., Kivisakk P., Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 2003;3:569–581. doi: 10.1038/nri1130.
    1. Ginhoux F., Lim S., Hoeffel G., Low D., Huber T. Origin and differentiation of microglia. Front. Cell Neurosci. 2013;7:45. doi: 10.3389/fncel.2013.00045.
    1. Harry G.J. Microglia during development and aging. Pharmacol. Ther. 2013;139:313–326. doi: 10.1016/j.pharmthera.2013.04.013.
    1. Papa L., Brophy G.M., Welch R.D., Lewis L.M., Braga C.F., Tan C.N., Ameli N.J., Lopez M.A., Haeussler C.A., Mendez Giordano D.I., et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers gfap and uch-l1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol. 2016;73:551–560. doi: 10.1001/jamaneurol.2016.0039.
    1. Zoltewicz J.S., Scharf D., Yang B., Chawla A., Newsom K.J., Fang L. Characterization of antibodies that detect human gfap after traumatic brain injury. Biomark. Insights. 2012;7:71–79. doi: 10.4137/BMI.S9873.
    1. Bogoslovsky T., Wilson D., Chen Y., Hanlon D., Gill J., Jeromin A., Song L., Moore C., Gong Y., Kenney K., et al. Increases of plasma levels of glial fibrillary acidic protein, tau, and amyloid beta up to 90 days after traumatic brain injury. J. Neurotrauma. 2017;34:66–73. doi: 10.1089/neu.2015.4333.
    1. Su E., Bell M.J., Kochanek P.M., Wisniewski S.R., Bayir H., Clark R.S., Adelson P.D., Tyler-Kabara E.C., Janesko-Feldman K.L., Berger R.P. Increased csf concentrations of myelin basic protein after tbi in infants and children: Absence of significant effect of therapeutic hypothermia. Neurocrit. Care. 2012;17:401–407. doi: 10.1007/s12028-012-9767-0.
    1. Raper D., Louveau A., Kipnis J. How do meningeal lymphatic vessels drain the cns? Trends Neurosci. 2016;39:581–586. doi: 10.1016/j.tins.2016.07.001.
    1. Louveau A., Da Mesquita S., Kipnis J. Lymphatics in neurological disorders: A neuro-lympho-vascular component of multiple sclerosis and alzheimer's disease? Neuron. 2016;91:957–973. doi: 10.1016/j.neuron.2016.08.027.
    1. Brait V.H., Arumugam T.V., Drummond G.R., Sobey C.G. Importance of t lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J. Cereb. Blood Flow Metab. 2012;32:598–611. doi: 10.1038/jcbfm.2012.6.
    1. Louveau A., Smirnov I., Keyes T.J., Eccles J.D., Rouhani S.J., Peske J.D., Derecki N.C., Castle D., Mandell J.W., Lee K.S., et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–341. doi: 10.1038/nature14432.
    1. Yang L., Kress B.T., Weber H.J., Thiyagarajan M., Wang B., Deane R., Benveniste H., Iliff J.J., Nedergaard M. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of csf tracer. J. Transl. Med. 2013;11:107. doi: 10.1186/1479-5876-11-107.
    1. Iliff J.J., Lee H., Yu M., Feng T., Logan J., Nedergaard M., Benveniste H. Brain-wide pathway for waste clearance captured by contrast-enhanced mri. J. Clin. Invest. 2013;123:1299–1309. doi: 10.1172/JCI67677.
    1. Xie L., Kang H., Xu Q., Chen M.J., Liao Y., Thiyagarajan M., O'Donnell J., Christensen D.J., Nicholson C., Iliff J.J., et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373–377. doi: 10.1126/science.1241224.
    1. Aspelund A., Antila S., Proulx S.T., Karlsen T.V., Karaman S., Detmar M., Wiig H., Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 2015;212:991–999. doi: 10.1084/jem.20142290.
    1. Li M., Li F., Luo C., Shan Y., Zhang L., Qian Z., Zhu G., Lin J., Feng H. Immediate splenectomy decreases mortality and improves cognitive function of rats after severe traumatic brain injury. J. Trauma. 2011;71:141–147. doi: 10.1097/TA.0b013e3181f30fc9.
    1. Chu W., Li M., Li F., Hu R., Chen Z., Lin J., Feng H. Immediate splenectomy down-regulates the mapk-nf-kappab signaling pathway in rat brain after severe traumatic brain injury. J. Trauma Acute Care Surg. 2013;74:1446–1453. doi: 10.1097/TA.0b013e31829246ad.
    1. Teixeira P.G., Karamanos E., Okoye O.T., Talving P., Inaba K., Lam L., Demetriades D. Splenectomy in patients with traumatic brain injury: Protective or harmful? A national trauma data bank analysis. J. Trauma Acute Care Surg. 2013;75:596–601. doi: 10.1097/TA.0b013e31829bb976.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir