Glial cells, including astrocytes and macrophages/microglia, are thought to modulate pathological states following spinal cord injury (SCI). In the present study, we evaluated the therapeutic effects of interferon-γ (IFN-γ), which is one of the cytokines regulating glial function, in a mouse contusive SCI model. We found that intraperitoneal injection of IFN-γ significantly facilitated locomotor improvement following SCI. Immunohistochemistry demonstrated that IFN-γ decreased the accumulation of chondroitin sulfate proteoglycans (CSPGs), which are critical axon outgrowth inhibitors produced by reactive astrocytes in the injured central nervous system (CNS). Quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting demonstrated that neurocan, one of several CSPGs, was reduced in the spinal cords of IFN-γ-treated mice compared to vehicle-treated mice. Consistently, IFN-γ inhibited the production of neurocan from activated astrocytes in vitro. In addition, IFN-γ treatment enhanced the number of serotonin-positive nerve fibers and myelinated nerve fibers around the lesion epicenter. We also found that glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor-1 (IGF-1) were upregulated post-SCI following IFN-γ treatment. Our results indicate that IFN-γ exhibits therapeutic effects in mouse contusive SCI, presumably by reducing CSPG expression from reactive astrocytes and increasing the expression of neurotrophic factors.
Get full access to this article
View all access options for this article.
References
1.
AsherR.A., MorgensternD.A., FidlerP.S., AdcockK.H., OohiraA., BraisteadJ.E., LevineJ.M., MargolisR.U., RogersJ.H., FawcettJ.W.2000. Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J. Neurosci., 20:2427–2438.
2.
BarrittA.W., DaviesM., MarchandF., HartleyR., GristJ., YipP., McMahonS.B., BradburyE.J.2006. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J. Neurosci., 26:10856–10867.
3.
BleschA., TuszynskiM.H.2003. Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination. J. Comp. Neurol., 467:403–417.
ButovskyO., ZivY., SchwartzA., LandaG., TalpalarA.E., PluchinoS., MartinoG., Michal SchwartzM.2006. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci., 31:149–160.
6.
ChengH., WuJ.P., TzengS.F.2002. Neuroprotection of glial cell line-derived neurotrophic factor in damaged spinal cords following contusive injury. J. Neurosci. Res., 69:397–405.
7.
DeumensR., KoopmansG.C., JoostenE.A.2005. Regeneration of descending axon tracts after spinal cord injury. Prog. Neurobiol., 77:57–89.
8.
DonnellyD.J., PopovichP.G.2008. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp. Neurol., 209:378–388.
9.
ElkabesS., DiCicco-BloomE.M., BlackI.B.1996. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci., 16:2508–2521.
10.
FouadK., SchnellL., BungeM.B., SchwabM.E., LiebscherT., PearseD.D.2005. Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J. Neurosci., 25:1169–1178.
11.
GenoveseT., MazzonE., CrisafulliC., Di PaolaR., MuiàC., BramantiP., CuzzocreaS.2006. Immunomodulatory effects of etanercept in an experimental model of spinal cord injury. J. Pharmacol. Exp. Ther., 316:1006–1016.
12.
GirardC., BemelmansA.P., DufourN., MalletJ., BachelinC., Nait-OumesmarB., Baron-Van EvercoorenA., LachapelleF.2005. Grafts of brain-derived neurotrophic factor and neurotrophin 3-transduced primate Schwann cells lead to functional recovery of the demyelinated mouse spinal cord. J. Neurosci., 25:7924–7933.
13.
GrillR., MuraiK., BleschA., GageF.H., TuszynskiM.H.1997. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J. Neurosci., 17:5560–5572.
14.
HashimotoM., NittaA., FukumitsuH., NomotoH., ShenL., FurukawaS.2005b. Inflammation-induced GDNF improves locomotor function after spinal cord injury. Neuroreport, 16:99–102.
15.
HashimotoM., NittaA., FukumitsuH., NomotoH., ShenL., FurukawaS.2005a. Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages. J. Neurosci. Res., 79:476–487.
JonesT.B., McDanielE.E., PopovichP.G.2005. Inflammatory-mediated injury and repair in the traumatically injured spinal cord. Curr. Pharm. Des., 11:1223–1236.
18.
KaurC., SivakumarV., DheenS.T., LingE.A.2006. Insulin-like growth factor I and II expression and modulation in amoeboid microglial cells by lipopolysaccharide and retinoic acid. Neuroscience, 138:1233–1244.
19.
KigerlK.A., McGaughyV.M., PopovichP.G.2006. Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J. Comp. Neurol., 494:578–594.
20.
KimJ.E., LiuB.P., ParkJ.H., StrittmatterS.M.2004. Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron, 44:439–451.
21.
KodaM., NishioY., KamadaT., SomeyaY., OkawaA., MoriC., YoshinagaK., OkadaS., MoriyaH., YamazakiM.2007. Granulocyte colony-stimulating factor (G-CSF) mobilizes bone marrow-derived cells into injured spinal cord and promotes functional recovery after compression-induced spinal cord injury in mice. Brain Res., 1149:223–231.
22.
Lazarov-SpieglerO., SolomonA.S., Zeev-BrannA.B., HirschbergD.L., LavieV., SchwartzM.1996. Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J., 10:1296–1302.
23.
LeeY.B., YuneT.Y., BaikS.Y., ShinY.H., DuS., RhimH., LeeE.B., KimY.C., ShinM.L., MarkelonisG.J., OhT.H.2000. Role of tumor necrosis factor-alpha in neuronal and glial apoptosis after spinal cord injury. Exp. Neurol., 166:190–195.
24.
MasonJ.L., XuanS., DragatsisI., EfstratiadisA., GoldmanJ.E.2003. Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. J. Neurosci., 23:7710–7718.
25.
McKeonR.J., JurynecM.J., BuckC.R.1999. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J. Neurosci., 19:10778–10788.
26.
McKeonR.J., SchreiberR.C., RudgeJ.S., SilverJ.1991. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J. Neurosci., 11:3398–3411.
27.
McTigueD.M., HornerP.J., StokesB.T., GageF.H.1998. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J. Neurosci., 18:5354–5365.
28.
NakajimaK., HondaS., TohyamaY., ImaiY., KohsakaS., KuriharaT.2001. Neurotrophin secretion from cultured microglia. J. Neurosci. Res., 65:322–331.
29.
NesicO., XuG.Y., McAdooD., HighK.W., HighK.W., HulseboschC., Perez-PolR.2001. IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J. Neurotrauma, 18:947–956.
30.
NishioY., KodaM., KamadaT., SomeyaY., KadotaR., MannojiC., MiyashitaT., OkadaS., OkawaA., MoriyaH., YamazakiM.2007. Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice. J. Neuropathol. Exp. Neurol., 66:724–731.
31.
OatwayM.A., ChenY., BruceJ.C., DekabanG.A., WeaverL.C.2005. Anti-CD11d integrin antibody treatment restores normal serotonergic projections to the dorsal, intermediate, and ventral horns of the injured spinal cord. J. Neurosci., 25:637–647.
32.
OzdinlerP.H., MacklisJ.D.2006. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat. Neurosci., 9:1371–1381.
33.
PopovichP.G., LongbrakeE.E.2008. Can the immune system be harnessed to repair the CNS? Nat. Rev. Neurosci., 9:481–493.
34.
PopovichP.G., WeiP., StokesB.T.1997. Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J. Comp. Neurol., 377:443–464.
35.
RapalinoO., Lazarov-SpieglerO., AgranovE., VelanG.J., YolesE., FraidakisM., SolomonA., GepsteinR., KatzA., BelkinM., HadaniM., SchwartzM.1998. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med., 4:814–821.
36.
SchroderK., HertzogP.J., RavasiT., HumeD.A.2004. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol., 75:163–189.
37.
SchwartzM., MoalemG., Leibowitz-AmitR., CohenI.R.1999. Innate and adaptive immune responses can be beneficial for CNS repair. Trends. Neurosci., 22:295–299.
38.
SharmaH.S.2005. Neuroprotective effects of neurotrophins and melanocortins in spinal cord injury: an experimental study in the rat using pharmacological and morphological approaches. Ann. NY Acad. Sci., 1053:407–421.
39.
ShechterR., LondonA., VarolC., RaposoC., CusimanoM., YovelG., RollsA., MackM., PluchinoS., MartinoG., JungS., SchwartzM.2009. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med., 6:e1000113.
40.
SmithG.M., StrunzC.2005. Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes. Glia, 52:209–218.
41.
SrogaJ.M., JonesT.B., KigerlK.A., McGaughyV.M., PopovichP.G.2003. Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J. Comp. Neurol., 462:223–240.
42.
StirlingD.P., LiuS., KubesP., YongV.W.2009. Depletion of Ly6G/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome. J. Neurosci., 29:753–764.
ZhouL., BaumgartnerB.J., Hill-FelbergS.J., McGowenL.R., ShineH.D.2003. Neurotrophin-3 expressed in situ induces axonal plasticity in the adult injured spinal cord. J. Neurosci., 23:1424–1231.
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.
