The innate immune response contributes to the inflammatory activity after traumatic brain injury (TBI). In the present study we identify macrophage-inducible C-type lectin (mincle) as a pattern recognition receptor that contributes to innate immunity in neurons after TBI. Here we report that mincle is activated by SAP130 in cortical neurons in culture, resulting in production of the inflammatory cytokine TNF. In addition, mincle and SAP130 are elevated in the brain and cerebrospinal fluid of humans after TBI and the brain of rodents after fluid percussion brain injury. Thus, these findings suggest the involvement of mincle to the pathology of TBI. Importantly, blocking mincle with a neutralizing antibody against mincle in cortical neurons in culture treated with SAP130 resulted in inhibition of mincle signaling and decreased TNF production. Therefore, our findings identify mincle as a contributor to the inflammatory response after TBI.
EngelhardtB., and RansohoffR.M. (2005). The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol., 26, 485–495.
3.
SchnellL., FearnS., SchwabM.E., PerryV.H., and AnthonyD.C. (1999). Cytokine-induced acute inflammation in the brain and spinal cord. J. Neuropathol. Exp. Neurol., 58, 245–254.
4.
BraitV.H., ArumugamT.V., DrummondG.R., and SobeyC.G. (2012). Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J. Cereb. Blood Flow Metab., 32, 598–611.
5.
CarlosT.M., ClarkR.S., Franicola-HigginsD., SchidingJ.K., and KochanekP.M. (1997). Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J. Leuk. Biol., 61, 279–285.
6.
LiaoY., LiuP., GuoF., ZhangZ.Y., and ZhangZ. (2013). Oxidative burst of circulating neutrophils following traumatic brain injury in human. PloS One, 8, e68963.
7.
SholkinaM.N., LebedevM.Y., BabaevA.A., BaryshnikovA.Y., and NovikovV.V. (2002). Effect of brain injury on immunophenotype of peripheral blood lymphocytes in rats. Russ. J. Immunol., 7, 365–370.
8.
AbulafiaD.P., de Rivero VaccariJ.P., LozanoJ.D., LotockiG., KeaneR.W., and DietrichW.D. (2009). Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J. Cereb. Blood Flow Metab., 29, 534–544.
9.
de Rivero VaccariJ.P., LotockiG., AlonsoO.F., BramlettH.M., DietrichW.D., and KeaneR.W. (2009). Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J. Cereb. Blood Flow Metab., 29, 1251–1261.
10.
de Rivero VaccariJ.P., LotockiG., MarcilloA.E., DietrichW.D., and KeaneR.W. (2008). A molecular platform in neurons regulates inflammation after spinal cord injury. J. Neurosci., 28, 3404–3414.
11.
AdamczakS.E. (2012). Molecular Recognition of DNA by the AIM2 Inflammasome Induces Neuronal Pyroptosis: Implications in Infection and Host Tissue Damage. Open Access Dissertations. Paper 854. Available at: http://scholarlyrepository.miami.edu/oa_dissertations/854
12.
de Rivero VaccariJ.P., BastienD., YurcisinG., PineauI., DietrichW.D., De KoninckY., KeaneR.W., and LacroixS. (2012). P2X4 receptors influence inflammasome activation after spinal cord injury. J. Neurosci., 32, 3058–3066.
13.
AdamczakS.E., de Rivero VaccariJ.P., DaleG., BrandF.J.3rd, NonnerD., BullockM.R., DahlG.P., DietrichW.D., and KeaneR.W. (2014). Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J. Cereb. Blood Flow Metab., 34, 621–629.
14.
OgdenC.A., deCathelineauA., HoffmannP.R., BrattonD., GhebrehiwetB., FadokV.A., and HensonP.M. (2001). C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med., 194, 781–795.
15.
YamasakiS., IshikawaE., SakumaM., HaraH., OgataK., and SaitoT. (2008). Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat. Immunol., 9, 1179–1188.
16.
CambiA. and FigdorC. (2009). Necrosis: C-type lectins sense cell death. Curr. Biol., 19, R375–R378.
17.
MenonS., TsugeT., DohmaeN., TakioK., and WeiN. (2008). Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome. BMC Biochem., 9, 1.
18.
WellsC.A., Salvage-JonesJ.A., LiX., HitchensK., ButcherS., MurrayR.Z., BeckhouseA.G., LoY.L., ManzaneroS., CobboldC., SchroderK., MaB., OrrS., StewartL., LebusD., SobieszczukP., HumeD.A., StowJ., BlanchardH. and AshmanR.B. (2008). The macrophage-inducible C-type lectin, mincle, is an essential component of the innate immune response to Candida albicans. J. Immunol., 180, 7404–7413.
19.
FanL., YoungP.R., BaroneF.C., FeuersteinG.Z., SmithD.H., and McIntoshT.K. (1996). Experimental brain injury induces differential expression of tumor necrosis factor-alpha mRNA in the CNS. Brain Res. Mol. Brain Res., 36, 287–291.
20.
RossS.A., HallidayM.I., CampbellG.C., ByrnesD.P., and RowlandsB.J. (1994). The presence of tumour necrosis factor in CSF and plasma after severe head injury. Br. J. Neurosurg., 8, 419–425.
21.
ShohamiE., BassR., WallachD., YaminA., and GallilyR. (1996). Inhibition of tumor necrosis factor alpha (TNFalpha) activity in rat brain is associated with cerebroprotection after closed head injury. J. Cereb. Blood Flow Metab., 16, 378–384.
22.
ShohamiE., GallilyR., MechoulamR., BassR., and Ben-HurT. (1997). Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant. J. Neuroimmunol., 72, 169–177.
23.
TaupinV., ToulmondS., SerranoA., BenavidesJ., and ZavalaF. (1993). Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of pre- and post-traumatic treatment with Ro5 4864, a peripheral-type(p site) benzodiazepine ligand. J. Neuroimmunol., 42, 177–185.
24.
VitarboE.A., ChatzipanteliK., KinoshitaK., TruettnerJ.S., AlonsoO.F., and DietrichW.D. (2004). Tumor necrosis factor alpha expression and protein levels after fluid percussion injury in rats: the effect of injury severity and brain temperature. Neurosurgery, 55, 416–425.
25.
SchneiderP., SchwenzerR., HaasE., MuhlenbeckF., SchubertG., ScheurichP., TschoppJ., and WajantH. (1999). TWEAK can induce cell death via endogenous TNF and TNF receptor 1. Eur. J. Immunol., 29, 1785–1792.
26.
SchwenzerR., SiemienskiK., LiptayS., SchubertG., PetersN., ScheurichP., SchmidR.M., and WajantH. (1999). The human tumor necrosis factor (TNF) receptor-associated factor 1 gene (TRAF1) is up-regulated by cytokines of the TNF ligand family and modulates TNF-induced activation of NF-kappaB and c-Jun N-terminal kinase. J. Biol. Chem., 274, 19368–19374.
27.
TomuraS., de Rivero VaccariJ.P., KeaneR.W., BramlettH.M., and DietrichW.D. (2012). Effects of therapeutic hypothermia on inflammasome signaling after traumatic brain injury. J. Cereb. Blood Flow Metab., 32, 1939–1947.
28.
de Rivero VaccariJ.P., SawayaM.E., BrandF.3rd, NusbaumB.P., BaumanA.J., BramlettH.M., DietrichW.D., and KeaneR.W. (2012). Caspase-1 level is higher in the scalp in androgenetic alopecia. Dermatol. Surg., 38, 1033–1039.
29.
SilvermanW.R., de Rivero VaccariJ.P., LocoveiS., QiuF., CarlssonS.K., ScemesE., KeaneR.W., and DahlG. (2009). The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J. Biol. Chem., 284, 18143–18151.
30.
BreenK., BrownA., BurdI., ChaiJ., FriedmanA., and ElovitzM.A. (2012). TLR-4-dependent and -independent mechanisms of fetal brain injury in the setting of preterm birth. Reprod. Sci., 19, 839–850.
31.
YuW.H., DongX.Q., HuY.Y., HuangM., and ZhangZ.Y. (2012). Ginkgolide B reduces neuronal cell apoptosis in the traumatic rat brain: possible involvement of toll-like receptor 4 and nuclear factor kappa B pathway. Phytother. Res., 26, 1838–1844.
32.
LeungP.Y., StevensS.L., PackardA.E., LessovN.S., YangT., ConradV.K., van den DungenN.N., SimonR.P., and Stenzel-PooreM.P. (2012). Toll-like receptor 7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism. Stroke, 43, 1383–1389.
33.
ZhangZ., ZhangZ.Y., WuY., and SchluesenerH.J. (2012). Immunolocalization of Toll-like receptors 2 and 4 as well as their endogenous ligand, heat shock protein 70, in rat traumatic brain injury. Neuroimmunomodulation, 19, 10–19.
34.
WangY.C., LinS., and YangQ.W. (2011). Toll-like receptors in cerebral ischemic inflammatory injury. J. Neuroinflammation, 8, 134.
35.
HuaF., WangJ., IshratT., WeiW., AtifF., SayeedI., and SteinD.G. (2011). Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. J. Neuroinflammation, 8, 42.
36.
MatsunagaI., and MoodyD.B. (2009). Mincle is a long sought receptor for mycobacterial cord factor. J. Exp. Med., 206, 2865–2868.
37.
StockerB.L., KhanA.A., CheeS.H., KamenaF., and TimmerM.S. (2014). On one leg: trehalose monoesters activate macrophages in a Mincle-dependant manner. Chembiochem., 15, 382–388.
38.
DubyakG.R. (2012). P2X7 receptor regulation of non-classical secretion from immune effector cells. Cell. Microbiol., 14, 1697–1706.
39.
AdamczakS., DaleG., de Rivero VaccariJ.P., BullockM.R., DietrichW.D., and KeaneR.W. (2012). Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J. Neurosurg., 117, 1119–1125.
40.
MootsR.J., and Naisbett-GroetB. (2012). The efficacy of biologic agents in patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors: a systematic review. Rheumatology, 51, 2252–2261.
41.
TobinickE., KimN.M., ReyzinG., Rodriguez-RomanacceH., and DePuyV. (2012). Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs, 26, 1051–1070.
42.
KaltsonoudisE., VoulgariP.V., KonitsiotisS. and DrososA.A. (2014). Demyelination and other neurological adverse events after anti-TNF therapy. Autoimmun. Rev., 13, 54–58.
43.
McCoyM.K., and TanseyM.G. (2008). TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J. Neuroinflammation, 5, 45.
44.
ShohamiE., GinisI., and HallenbeckJ.M. (1999). Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev., 10, 119–130.
45.
SriramK., and O'CallaghanJ.P. (2007). Divergent roles for tumor necrosis factor-alpha in the brain. J. Neuroimmune Pharmacol., 2, 140–153.
46.
ScherbelU., RaghupathiR., NakamuraM., SaatmanK.E., TrojanowskiJ.Q., NeugebauerE., MarinoM.W., and McIntoshT.K. (1999). Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc. Natl. Acad. Sci. U. S. A., 96, 8721–8726.
47.
StahelP.F., ShohamiE., YounisF.M., KariyaK., OttoV.I., LenzlingerP.M., GrosjeanM.B., EugsterH.P., TrentzO., KossmannT., and Morganti-KossmannM.C. (2000). Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines. J. Cereb. Blood Flow Metab., 20, 369–380.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
