Tailored Therapeutic Doses of Dexmedetomidine in Evolving Neuroinflammation after Traumatic Brain Injury.
Dexmedetomidine
Inflammasome
Microglia
NLRP3
Neuroinflammation
T cells
Traumatic brain injury
Journal
Neurocritical care
ISSN: 1556-0961
Titre abrégé: Neurocrit Care
Pays: United States
ID NLM: 101156086
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
12
05
2021
accepted:
13
10
2021
pubmed:
17
11
2021
medline:
20
5
2022
entrez:
16
11
2021
Statut:
ppublish
Résumé
Understanding the secondary damage mechanisms of traumatic brain injury (TBI) is essential for developing new therapeutic approaches. Neuroinflammation has a pivotal role in secondary brain injury after TBI. Activation of NLRP3 inflammasome complexes results in the secretion of proinflammatory mediators and, in addition, later in the response, microglial activation and migration of the peripheral immune cells into the injured brain are observed. Therefore, these components involved in the inflammatory process are becoming a new treatment target in TBI. Dexmedetomidine (Dex) is an effective drug, widely used over the past few years in neurocritical care units and during surgical operations for sedation and analgesia, and has anti-inflammatory effects, which are shown in in vivo studies. The aim of this original research is to discuss the anti-inflammatory effects of different Dex doses over time in TBI. Brain injury was performed by using a weight-drop model. Half an hour after the trauma, intraperitoneal saline was injected into the control groups and 40 and 200 μg/kg of Dex were given to the drug groups. Neurological evaluations were performed with the modified Neurological Severity Score before being killed. Then, the mice were killed on the first or the third day after TBI and histopathologic (hematoxylin-eosin) and immunofluorescent (Iba1, NLRP3, interleukin-1β, and CD3) findings of the brain tissues were examined. Nonparametric data were analyzed by using the Kruskal-Wallis test for multiple comparisons, and the Mann-Whitney U-test was done for comparing two groups. The results are presented as mean ± standard error of mean. The results showed that low doses of Dex suppress NLRP3 and interleukin-1β in both terms. Additionally, high doses of Dex cause a remarkable decrease in the migration and motility of microglial cells and T cells in the late phase following TBI. Interestingly, the immune cells were influenced by only high-dose Dex in the late phase of TBI and it also improves neurologic outcome in the same period. In the mice head trauma model, different doses of Dex attenuate neuroinflammation by suppressing distinct components of the neuroinflammatory process in a different timecourse that contributes to neurologic recovery. These results suggest that Dex may be an appropriate choice for sedation and analgesia in patients with TBI.
Sections du résumé
BACKGROUND
Understanding the secondary damage mechanisms of traumatic brain injury (TBI) is essential for developing new therapeutic approaches. Neuroinflammation has a pivotal role in secondary brain injury after TBI. Activation of NLRP3 inflammasome complexes results in the secretion of proinflammatory mediators and, in addition, later in the response, microglial activation and migration of the peripheral immune cells into the injured brain are observed. Therefore, these components involved in the inflammatory process are becoming a new treatment target in TBI. Dexmedetomidine (Dex) is an effective drug, widely used over the past few years in neurocritical care units and during surgical operations for sedation and analgesia, and has anti-inflammatory effects, which are shown in in vivo studies. The aim of this original research is to discuss the anti-inflammatory effects of different Dex doses over time in TBI.
METHODS
Brain injury was performed by using a weight-drop model. Half an hour after the trauma, intraperitoneal saline was injected into the control groups and 40 and 200 μg/kg of Dex were given to the drug groups. Neurological evaluations were performed with the modified Neurological Severity Score before being killed. Then, the mice were killed on the first or the third day after TBI and histopathologic (hematoxylin-eosin) and immunofluorescent (Iba1, NLRP3, interleukin-1β, and CD3) findings of the brain tissues were examined. Nonparametric data were analyzed by using the Kruskal-Wallis test for multiple comparisons, and the Mann-Whitney U-test was done for comparing two groups. The results are presented as mean ± standard error of mean.
RESULTS
The results showed that low doses of Dex suppress NLRP3 and interleukin-1β in both terms. Additionally, high doses of Dex cause a remarkable decrease in the migration and motility of microglial cells and T cells in the late phase following TBI. Interestingly, the immune cells were influenced by only high-dose Dex in the late phase of TBI and it also improves neurologic outcome in the same period.
CONCLUSIONS
In the mice head trauma model, different doses of Dex attenuate neuroinflammation by suppressing distinct components of the neuroinflammatory process in a different timecourse that contributes to neurologic recovery. These results suggest that Dex may be an appropriate choice for sedation and analgesia in patients with TBI.
Identifiants
pubmed: 34782991
doi: 10.1007/s12028-021-01381-3
pii: 10.1007/s12028-021-01381-3
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Interleukin-1beta
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Dexmedetomidine
67VB76HONO
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
802-814Informations de copyright
© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.
Références
Menon DK, Schwab K, Wright DW, Maas AI, Demographics, Clinical Assessment Working Group of the I, et al. Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil. 2010;91(11):1637–40.
Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7(8):728–41.
pubmed: 18635021
doi: 10.1016/S1474-4422(08)70164-9
Andelic N. The epidemiology of traumatic brain injury. The Lancet Neurology. 2013;12(1):28–9.
pubmed: 23177533
doi: 10.1016/S1474-4422(12)70294-6
McKee AC, Daneshvar DH. The neuropathology of traumatic brain injury. Handb Clin Neurol. 2015;127:45–66.
pubmed: 25702209
pmcid: 4694720
doi: 10.1016/B978-0-444-52892-6.00004-0
Chiu CC, Liao YE, Yang LY, Wang JY, Tweedie D, Karnati HK, et al. Neuroinflammation in animal models of traumatic brain injury. J Neurosci Methods. 2016;272:38–49.
pubmed: 27382003
pmcid: 5201203
doi: 10.1016/j.jneumeth.2016.06.018
Ghajar J. Traumatic brain injury. The Lancet. 2000;356(9233):923–9.
doi: 10.1016/S0140-6736(00)02689-1
Werner C, Engelhard K. Pathophysiology of traumatic brain injury. BJA Br J Anaesth. 2007;99(1):4–9.
pubmed: 17573392
doi: 10.1093/bja/aem131
Graham DI, McIntosh TK, Maxwell WL, Nicoll JA. Recent advances in neurotrauma. J Neuropathol Exp Neurol. 2000;59(8):641–51.
pubmed: 10952055
doi: 10.1093/jnen/59.8.641
Song L, Pei L, Yao S, Wu Y, Shang Y. NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies. Front Cell Neurosci. 2017;11:63.
pubmed: 28337127
pmcid: 5343070
Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, et al. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol. 1991;20(Suppl 2):S28-35.
pubmed: 1833351
doi: 10.1093/ije/20.Supplement_2.S28
Webster SJ, Van Eldik LJ, Watterson DM, Bachstetter AD. Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment. J Neurosci. 2015;35(16):6554–69.
pubmed: 25904805
pmcid: 4405562
doi: 10.1523/JNEUROSCI.0291-15.2015
Harnod D, Harnod T, Lin CL, Shen WC, Kao CH. Increased risks of suicide attempt and suicidal drug overdose following admission for head injury in patients with depression. Int J Environ Res Public Health. 2019;16(19):3524.
pmcid: 6801720
doi: 10.3390/ijerph16193524
Holsinger T, Steffens DC, Phillips C, Helms MJ, Havlik RJ, Breitner JC, et al. Head injury in early adulthood and the lifetime risk of depression. Arch Gen Psychiatry. 2002;59(1):17–22.
pubmed: 11779276
doi: 10.1001/archpsyc.59.1.17
Mas F, Prichep LS, Alper K. Treatment resistant depression in a case of minor head injury: an electrophysiological hypothesis. Clin Electroencephalogr. 1993;24(3):118–22.
pubmed: 8403443
doi: 10.1177/155005949302400309
Salmond CH, Menon DK, Chatfield DA, Pickard JD, Sahakian BJ. Cognitive reserve as a resilience factor against depression after moderate/severe head injury. J Neurotrauma. 2006;23(7):1049–58.
pubmed: 16866618
doi: 10.1089/neu.2006.23.1049
Weiner MW, Harvey D, Hayes J, Landau SM, Aisen PS, Petersen RC, et al. Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer’s disease in Vietnam Veterans using the Alzheimer’s disease neuroimaging initiative: preliminary report. Alzheimers Dement (N Y). 2017;3(2):177–88.
doi: 10.1016/j.trci.2017.02.005
Chase A. Parkinson disease: traumatic brain injury increases the risk of Parkinson disease. Nat Rev Neurol. 2015;11(4):184.
pubmed: 25799936
doi: 10.1038/nrneurol.2015.39
Gardner RC, Burke JF, Nettiksimmons J, Goldman S, Tanner CM, Yaffe K. Traumatic brain injury in later life increases risk for Parkinson disease. Ann Neurol. 2015;77(6):987–95.
pubmed: 25726936
pmcid: 4447556
doi: 10.1002/ana.24396
Kiernan PT, Montenigro PH, Solomon TM, McKee AC. Chronic traumatic encephalopathy: a neurodegenerative consequence of repetitive traumatic brain injury. Semin Neurol. 2015;35(1):20–8.
pubmed: 25714864
doi: 10.1055/s-0035-1545080
Filiano AJ, Gadani SP, Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci. 2017;18(6):375–84.
pubmed: 28446786
pmcid: 5823005
doi: 10.1038/nrn.2017.39
Freeman LC, Ting JP. The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem. 2016;136(Suppl 1):29–38.
pubmed: 26119245
doi: 10.1111/jnc.13217
Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW. Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg. 2012;117(6):1119–25.
pubmed: 23061392
pmcid: 3576729
doi: 10.3171/2012.9.JNS12815
Donat CK, Scott G, Gentleman SM, Sastre M. Microglial activation in traumatic brain injury. Front Aging Neurosci. 2017;9:208.
pubmed: 28701948
pmcid: 5487478
doi: 10.3389/fnagi.2017.00208
Smith C, Gentleman SM, Leclercq PD, Murray LS, Griffin WS, Graham DI, et al. The neuroinflammatory response in humans after traumatic brain injury. Neuropathol Appl Neurobiol. 2013;39(6):654–66.
pubmed: 23231074
doi: 10.1111/nan.12008
Galgano M, Toshkezi G, Qiu X, Russell T, Chin L, Zhao LR. Traumatic brain injury: current treatment strategies and future endeavors. Cell Transplant. 2017;26(7):1118–30.
pubmed: 28933211
pmcid: 5657730
doi: 10.1177/0963689717714102
Abou El Fadl MH, O’Phelan KH. Management of traumatic brain injury: an update. Neurosurg Clin N Am. 2018;29(2):213–21.
pubmed: 29502712
doi: 10.1016/j.nec.2017.11.002
Jain KK. Neuroprotection in traumatic brain injury. Drug Discov Today. 2008;13(23–24):1082–9.
pubmed: 18848641
doi: 10.1016/j.drudis.2008.09.006
Pearn ML, Niesman IR, Egawa J, Sawada A, Almenar-Queralt A, Shah SB, et al. Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics. Cell Mol Neurobiol. 2017;37(4):571–85.
pubmed: 27383839
doi: 10.1007/s10571-016-0400-1
Corps KN, Roth TL, McGavern DB. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol. 2015;72(3):355–62.
pubmed: 25599342
pmcid: 5001842
doi: 10.1001/jamaneurol.2014.3558
Wang L, Liu H, Zhang L, Wang G, Zhang M, Yu Y. Neuroprotection of dexmedetomidine against cerebral ischemia-reperfusion injury in rats: involved in inhibition of NF-kappaB and inflammation response. Biomol Ther (Seoul). 2017;25(4):383–9.
doi: 10.4062/biomolther.2015.180
Luo C, Ouyang MW, Fang YY, Li SJ, Zhou Q, Fan J, et al. Dexmedetomidine protects mouse brain from ischemia-reperfusion injury via inhibiting neuronal autophagy through up-regulating HIF-1alpha. Front Cell Neurosci. 2017;11:197.
pubmed: 28729825
pmcid: 5498477
doi: 10.3389/fncel.2017.00197
Bell MT, Agoston VA, Freeman KA, Puskas F, Herson PS, Mares J, et al. Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia. J Vasc Surg. 2014;59(4):1090–7.
pubmed: 23850057
doi: 10.1016/j.jvs.2013.04.050
Ma J, Zhang XL, Wang CY, Lin Z, Tao JR, Liu HC. Dexmedetomidine alleviates the spinal cord ischemia-reperfusion injury through blocking mast cell degranulation. Int J Clin Exp Med. 2015;8(9):14741–9.
pubmed: 26628956
pmcid: 4658845
Rong H, Zhao Z, Feng J, Lei Y, Wu H, Sun R, et al. The effects of dexmedetomidine pretreatment on the pro- and anti-inflammation systems after spinal cord injury in rats. Brain Behav Immun. 2017;64:195–207.
pubmed: 28302458
doi: 10.1016/j.bbi.2017.03.006
Liu Z, Wang Y, Wang Y, Ning Q, Zhang Y, Gong C, et al. Dexmedetomidine attenuates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway. Int Immunopharmacol. 2016;35:210–6.
pubmed: 27074053
doi: 10.1016/j.intimp.2016.04.003
Liu W, Yu W, Weng Y, Wang Y, Sheng M. Dexmedetomidine ameliorates the inflammatory immune response in rats with acute kidney damage. Exp Ther Med. 2017;14(4):3602–8.
pubmed: 29042954
pmcid: 5639432
doi: 10.3892/etm.2017.4954
Sun Y, Jiang C, Jiang J, Qiu L. Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway. Clin Exp Pharmacol Physiol. 2017;44(9):946–53.
pubmed: 28556946
doi: 10.1111/1440-1681.12791
Chen Z, Ding T, Ma CG. Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice. Biochem Biophys Res Commun. 2017;493(2):1143–50.
pubmed: 28784305
doi: 10.1016/j.bbrc.2017.08.017
Li Y, Pan Y, Gao L, Lu G, Zhang J, Xie X, et al. Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression. Biochem Biophys Res Commun. 2018;495(4):2439–47.
pubmed: 29269298
doi: 10.1016/j.bbrc.2017.12.090
Cheng F, Yan FF, Liu YP, Cong Y, Sun KF, He XM. Dexmedetomidine inhibits the NF-kappaB pathway and NLRP3 inflammasome to attenuate papain-induced osteoarthritis in rats. Pharm Biol. 2019;57(1):649–59.
pubmed: 31545916
pmcid: 6764405
doi: 10.1080/13880209.2019.1651874
Jiang WW, Wang QH, Liao YJ, Peng P, Xu M, Yin LX. Effects of dexmedetomidine on TNF-alpha and interleukin-2 in serum of rats with severe craniocerebral injury. BMC Anesthesiol. 2017;17(1):130.
pubmed: 28931374
pmcid: 5607498
doi: 10.1186/s12871-017-0410-7
Schoeler M, Loetscher PD, Rossaint R, Fahlenkamp AV, Eberhardt G, Rex S, et al. Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol. 2012;12:20.
pubmed: 22494498
pmcid: 3350422
doi: 10.1186/1471-2377-12-20
Humble SS, Wilson LD, Leath TC, Marshall MD, Sun DZ, Pandharipande PP, et al. ICU sedation with dexmedetomidine after severe traumatic brain injury. Brain Inj. 2016;30(10):1266–70.
pubmed: 27458990
pmcid: 5160042
doi: 10.1080/02699052.2016.1187289
Ma D, Rajakumaraswamy N, Maze M. alpha2-Adrenoceptor agonists: shedding light on neuroprotection? Br Med Bull. 2004;71:77–92.
pubmed: 15684247
doi: 10.1093/bmb/ldh036
Shen M, Wang S, Wen X, Han XR, Wang YJ, Zhou XM, et al. Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomed Pharmacother. 2017;95:885–93.
pubmed: 28903184
doi: 10.1016/j.biopha.2017.08.125
Irrera N, Russo M, Pallio G, Bitto A, Mannino F, Minutoli L, et al. The role of NLRP3 inflammasome in the pathogenesis of traumatic brain injury. Int J Mol Sci. 2020;21(17):6204.
pmcid: 7503761
doi: 10.3390/ijms21176204
Gentleman D. Causes and effects of systemic complications among severely head injured patients transferred to a neurosurgical unit. Int Surg. 1992;77(4):297–302.
pubmed: 1478813
Wu J, Vogel T, Gao X, Lin B, Kulwin C, Chen J. Neuroprotective effect of dexmedetomidine in a murine model of traumatic brain injury. Sci Rep. 2018;8(1):4935.
pubmed: 29563509
pmcid: 5862953
doi: 10.1038/s41598-018-23003-3
Dahmani S, Paris A, Jannier V, Hein L, Rouelle D, Scholz J, et al. Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an alpha 2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors. Anesthesiology. 2008;108(3):457–66.
pubmed: 18292683
doi: 10.1097/ALN.0b013e318164ca81
Zhu YM, Wang CC, Chen L, Qian LB, Ma LL, Yu J, et al. Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res. 2013;1494:1–8.
pubmed: 23219579
doi: 10.1016/j.brainres.2012.11.047
Talke P, Bickler PE. Effects of dexmedetomidine on hypoxia-evoked glutamate release and glutamate receptor activity in hippocampal slices. Anesthesiology. 1996;85(3):551–7.
pubmed: 8853085
doi: 10.1097/00000542-199609000-00014
Wang D, Xu X, Wu YG, Lyu L, Zhou ZW, Zhang JN. Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms. Neural Regen Res. 2018;13(5):819–26.
pubmed: 29863012
pmcid: 5998618
doi: 10.4103/1673-5374.232529
Riquelme JA, Westermeier F, Hall AR, Vicencio JM, Pedrozo Z, Ibacache M, et al. Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism. Pharmacol Res. 2016;103:318–27.
pubmed: 26607864
doi: 10.1016/j.phrs.2015.11.004
Liu Z, Wang Y, Ning Q, Gong C, Zhang Y, Zhang L, et al. The role of spleen in the treatment of experimental lipopolysaccharide-induced sepsis with dexmedetomidine. SpringerPlus. 2015;4:800.
pubmed: 26702389
pmcid: 4688290
doi: 10.1186/s40064-015-1598-y
Akpinar O, Naziroglu M, Akpinar H. Different doses of dexmedetomidine reduce plasma cytokine production, brain oxidative injury, PARP and caspase expression levels but increase liver oxidative toxicity in cerebral ischemia-induced rats. Brain Res Bull. 2017;130:1–9.
pubmed: 28007581
doi: 10.1016/j.brainresbull.2016.12.005
Si Y, Zhang Y, Han L, Chen L, Xu Y, Sun F, et al. Dexmedetomidine acts via the JAK2/STAT3 pathway to attenuate isoflurane-induced neurocognitive deficits in senile mice. PLoS ONE. 2016;11(10):e0164763.
pubmed: 27768775
pmcid: 5074497
doi: 10.1371/journal.pone.0164763
Yeh CH, Hsieh LP, Lin MC, Wei TS, Lin HC, Chang CC, et al. Dexmedetomidine reduces lipopolysaccharide induced neuroinflammation, sickness behavior, and anhedonia. PLoS ONE. 2018;13(1):e0191070.
pubmed: 29351316
pmcid: 5774758
doi: 10.1371/journal.pone.0191070
Zhu YJ, Peng K, Meng XW, Ji FH. Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model. Brain Res. 2016;1644:1–8.
pubmed: 27163720
doi: 10.1016/j.brainres.2016.04.074
Kutanis D, Erturk E, Besir A, Demirci Y, Kayir S, Akdogan A, et al. Dexmedetomidine acts as an oxidative damage prophylactic in rats exposed to ionizing radiation. J Clin Anesth. 2016;34:577–85.
pubmed: 27687454
doi: 10.1016/j.jclinane.2016.06.031
Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, et al. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol. 2007;204(1):220–33.
pubmed: 17188268
doi: 10.1016/j.expneurol.2006.10.013
Madathil SK, Wilfred BS, Urankar SE, Yang W, Leung LY, Gilsdorf JS, et al. Early microglial activation following closed-head concussive injury is dominated by pro-inflammatory M-1 type. Front Neurol. 2018;9:964.
pubmed: 30498469
pmcid: 6249371
doi: 10.3389/fneur.2018.00964
Carbonell WS, Murase S, Horwitz AF, Mandell JW. Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5: an in situ time-lapse confocal imaging study. J Neurosci. 2005;25(30):7040–7.
pubmed: 16049180
pmcid: 6724831
doi: 10.1523/JNEUROSCI.5171-04.2005
Liu HD, Li W, Chen ZR, Hu YC, Zhang DD, Shen W, et al. Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res. 2013;38(10):2072–83.
pubmed: 23892989
doi: 10.1007/s11064-013-1115-z
O’Brien WT, Pham L, Symons GF, Monif M, Shultz SR, McDonald SJ. The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target. J Neuroinflammation. 2020;17(1):104.
pubmed: 32252777
pmcid: 7137518
doi: 10.1186/s12974-020-01778-5
Fann DY, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4:e790.
pubmed: 24008734
doi: 10.1038/cddis.2013.326
Ma Q, Chen S, Hu Q, Feng H, Zhang JH, Tang J. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol. 2014;75(2):209–19.
pubmed: 24273204
pmcid: 4386653
doi: 10.1002/ana.24070
Diaz MF, Horton PD, Kumar A, Livingston M, Mohammadalipour A, Xue H, et al. Injury intensifies T cell mediated graft-versus-host disease in a humanized model of traumatic brain injury. Sci Rep. 2020;10(1):10729.
pubmed: 32612177
pmcid: 7330041
doi: 10.1038/s41598-020-67723-x
Soares HD, Hicks RR, Smith D, McIntosh TK. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci. 1995;15(12):8223–33.
pubmed: 8613756
pmcid: 6577921
doi: 10.1523/JNEUROSCI.15-12-08223.1995
Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75.
pubmed: 23435331
doi: 10.1038/nri3399
Carlos TM, Clark RS, Franicola-Higgins D, Schiding JK, Kochanek PM. Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J Leukoc Biol. 1997;61(3):279–85.
pubmed: 9060450
doi: 10.1002/jlb.61.3.279
Schwarzmaier SM, Plesnila N. Contributions of the immune system to the pathophysiology of traumatic brain injury—evidence by intravital microscopy. Front Cell Neurosci. 2014;8:358.
pubmed: 25408636
pmcid: 4219391
doi: 10.3389/fncel.2014.00358
Kramer TJ, Hack N, Bruhl TJ, Menzel L, Hummel R, Griemert EV, et al. Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-gamma gene expression in acute experimental traumatic brain injury. J Neuroinflammation. 2019;16(1):163.
pubmed: 31383034
pmcid: 6683516
doi: 10.1186/s12974-019-1550-0