Neural stem/progenitor cells (NSCs/NPCs) are present in different locations in the central nervous system. In the subgranular zone (SGZ) there is a constant generation of new neurons under normal conditions. New neurons are also formed from the subventricular zone (SVZ) NSCs, and they migrate anteriorly as neuroblast to the olfactory bulb in rodents, whereas in humans migration is directed toward striatum. Most CNS injuries elicit proliferation and migration of the NSCs toward the injury site, indicating the activation of a regenerative response. However, regeneration from NSC is incomplete, and this could be due to detrimental cues encountered during inflammation. Different CNS diseases and trauma cause activation of the innate and adaptive immune responses that influence the NSCs. Furthermore, NSCs in the brain react differently to inflammatory cues than their counterparts in the spinal cord. In this review, we have summarized the effects of inflammation on NSCs in relation to their origin and briefly described the NSC activity during different neurological diseases or experimental models.
AdrianEKJrWalkerBE. 1962. Incorporation of thymidine-H3 by cells in normal and injured mouse spinal cord. J Neuropathol Exp Neurol21:597–609.
2.
AllenE. 1912. The cessation of mitosis in the central nervous system of the albino rat. J Comp Neurol19:547–68.
3.
ArvidssonACollinTKirikDKokaiaZLindvallO. 2002. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med8:963–70.
4.
ArvidssonACovacuRSankavaram RagavanSSvenssonMBrundinL. 2015. Long-distance effects of inflammation on differentiation of adult spinal cord neural stem/progenitor cells. J Neuroimmunol288:47-55.
5.
ArvidssonLFagerlundMJaffNOssoinakAJanssonKHagerstrandA, and others. 2011. Distribution and characterization of progenitor cells within the human filum terminale. PLoS One6(11):e27393.
6.
AzariMFProfyrisCZangDWPetratosSCheemaSS. 2005. Induction of endogenous neural precursors in mouse models of spinal cord injury and disease. Eur J Neurol12:638–48.
7.
Barnabe-HeiderFGoritzCSabelstromHTakebayashiHPfriegerFWMeletisK, and others. 2010. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell7:470–82.
8.
BaronRNemirovskyAHarpazICohenHOwensTMonsonegoA. 2008. IFN-γ enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease. FASEB J22:2843–52.
9.
BauerSPattersonPH. 2006. Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain. J Neurosci26:12089–99.
10.
BergmannOLieblJBernardSAlkassKYeungMSSteierP, and others. 2012. The age of olfactory bulb neurons in humans. Neuron74:634–9.
11.
BergslandMCovacuRPérez EstradaCSvenssonMBrundinL. 2014. Nitric oxide-induced neuronal to glial lineage fate-change depends on NRSF/REST function in neural progenitor cells. Stem Cells32:2539–49.
BoLDawsonTMWesselinghSMorkSChoiSKongPA, and others. 1994. Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol36:778–86.
14.
BoekhoornKJoelsMLucassenPJ. 2006. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis24:1–14.
15.
BrundinLBrismarHDanilovAIOlssonTJohanssonCB. 2003. Neural stem cells: a potential source for remyelination in neuroinflammatory disease. Brain Pathol13:322–8.
16.
BuffoARiteITripathiPLepierAColakDHornAP, and others. 2008. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A105:3581–6.
17.
CameronHATanapatPGouldE. 1998. Adrenal steroids and N-methyl-d-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience82:349–54.
18.
CarlenMMeletisKGoritzCDarsaliaVEvergrenETanigakiK, and others. 2009. Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci12:259–67.
19.
ChapmanKZGeRMonniETatarishviliJAhleniusHArvidssonA, and others. 2015. Inflammation without neuronal death triggers striatal neurogenesis comparable to stroke. Neurobiol Dis83:1–15.
20.
CovacuRArvidssonLAnderssonAKhademiMErlandsson-HarrisHHarrisRA, and others. 2009. TLR activation induces TNF-α production from adult neural stem/progenitor cells. J Immunol182:6889–95.
21.
CovacuRDanilovAIRasmussenBSHallenKMoeMCLobellA, and others. 2006. Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis. Stem Cells24:2792–800.
22.
CovacuRPérez EstradaCArvidssonLSvenssonMBrundinL. 2014. Change of fate commitment in adult neural progenitor cells subjected to chronic inflammation. J Neurosci34:11571–82.
23.
DanilovAICovacuRMoeMCLangmoenIAJohanssonCBOlssonT, and others. 2006. Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis. Eur J Neurosci23:394–400.
24.
DoetschFCailleILimDAGarcia-VerdugoJMAlvarez-BuyllaA. 1999a. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell97:703–16.
25.
DoetschFGarcia-VerdugoJMAlvarez-BuyllaA. 1997. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci17:5046–61.
26.
DoetschFGarcia-VerdugoJMAlvarez-BuyllaA. 1999b. Regeneration of a germinal layer in the adult mammalian brain. Proc Natl Acad Sci U S A96:11619–24.
27.
DromardCGuillonHRigauVRipollCSabourinJCPerrinFE, and others. 2008. Adult human spinal cord harbors neural precursor cells that generate neurons and glial cells in vitro. J Neurosci Res86:1916–26.
28.
EinsteinOFainsteinNVakninIMizrachi-KolRReihartzEGrigoriadisN, and others. 2007. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol61:209–18.
29.
EinsteinOKarussisDGrigoriadisNMizrachi-KolRReinhartzEAbramskyO, and others. 2003. Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci24:1074–82.
30.
EkdahlCTClaasenJHBondeSKokaiaZLindvallO. 2003. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A100:13632–7.
31.
ErikssonPSPerfilievaEBjork-ErikssonTAlbornAMNordborgCPetersonDA, and others. 1998. Neurogenesis in the adult human hippocampus. Nat Med4:1313–7.
32.
ErnstAAlkassKBernardSSalehpourMPerlSTisdaleJ, and others. 2014. Neurogenesis in the striatum of the adult human brain. Cell156:1072–83.
33.
FrisenJJohanssonCBTorokCRislingMLendahlU. 1995. Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol131:453–64.
34.
FujimuraMGascheYMorita-FujimuraYMassengaleJKawaseMChanPH. 1999. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res842:92–100.
35.
GaoZUreKDingPNashaatMYuanLMaJ, and others. 2011. The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci31:9772–86.
36.
GemmaCBachstetterADColeMJFisterMHudsonCBickfordPC. 2007. Blockade of caspase-1 increases neurogenesis in the aged hippocampus. Eur J Neurosci26:2795–803.
37.
GiannakopoulouAGrigoriadisNBekiariCLourbopoulosADoriITsingotjidouAS, and others. 2013. Acute inflammation alters adult hippocampal neurogenesis in a multiple sclerosis mouse model. J Neurosci Res91:890–900.
38.
GoldRLiningtonCLassmannH. 2006. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain129(Pt 8):1953–71.
39.
Gomez-NicolaDValle-ArgosBPallas-BazarraNNieto-SampedroM. 2011. Interleukin-15 regulates proliferation and self-renewal of adult neural stem cells. Mol Biol Cell22:1960–70.
40.
GrigoriadisNvan PeschV. 2015. A basic overview of multiple sclerosis immunopathology. Eur J Neurol22(Suppl 2):3–13.
41.
GuanYJiangZCiricBRostamiAMZhangGX. 2008. Upregulation of chemokine receptor expression by IL-10/IL-4 in adult neural stem cells. Exp Mol Pathol85:232–6.
42.
HeldmannUThoredPClaasenJArvidssonAKokaiaZLindvallO. 2005. TNF-α antibody infusion impairs survival of stroke-generated neuroblasts in adult rat brain. Exp Neurol196:204–8.
43.
HenekaMTGolenbockDTLatzE. 2015. Innate immunity in Alzheimer’s disease. Nat Immunol16:229–36.
44.
HornerPJPowerAEKempermannGKuhnHGPalmerTDWinklerJ, and others. 2000. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J Neurosci20:2218–28.
45.
HurnPDSubramanianSParkerSMAfentoulisMEKalerLJVandenbarkAA, and others. 2007. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab27:1798–805.
46.
IadecolaCAnratherJ. 2011. The immunology of stroke: from mechanisms to translation. Nat Med17:796–808.
47.
IliffJJWangMLiaoYPloggBAPengWGundersenGA, and others. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med4(147):147ra111.
48.
IosifREAhleniusHEkdahlCTDarsaliaVThoredPJovingeS, and others. 2008. Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1. J Cereb Blood Flow Metab. 28:1574–87.
49.
IosifREEkdahlCTAhleniusHPronkCJBondeSKokaiaZ, and others. 2006. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci26:9703–12.
50.
JohanssonCBMommaSClarkeDLRislingMLendahlUFrisenJ. 1999. Identification of a neural stem cell in the adult mammalian central nervous system. Cell96:25–34.
51.
KangM.KKangSK. 2008. Interleukin-6 induces proliferation in adult spinal cord–derived neural progenitors via the JAK2/STAT3 pathway with EGF-induced MAPK phosphorylation. Cell Prolif41:377–92.
52.
KempermannGKuhnHGGageFH. 1997. More hippocampal neurons in adult mice living in an enriched environment. Nature386:493–5.
53.
KigerlKAGenselJCAnkenyDPAlexanderJKDonnellyDJPopovichPG. 2009. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci29:13435–44.
54.
KivisakkPMahadDJCallahanMKTrebstCTuckyBWeiT, and others. 2003. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A100:8389–94.
55.
KokoevaMVYinHFlierJS. 2005. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science310:679–83.
56.
KokovayEWangYKusekGWursterRLedermanPLowryN, and others. 2012. VCAM1 is essential to maintain the structure of the SVZ niche and acts as an environmental sensor to regulate SVZ lineage progression. Cell Stem Cell11:220–30.
57.
KonatGWKielianTMarriottI. 2006. The role of Toll-like receptors in CNS response to microbial challenge. J Neurochem99:1–12.
58.
KooJWDumanRS. 2008. IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A105:751–6.
59.
KulbatskiITatorCH. 2009. Region-specific differentiation potential of adult rat spinal cord neural stem/precursors and their plasticity in response to in vitro manipulation. J Histochem Cytochem57:405–23.
60.
LacroixSHamiltonLKVaugeoisABeaudoinSBreault-DugasCPineauI, and others. 2014. Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions. PLoS One9(1):e85916.
61.
LangrishCLChenYBlumenscheinWMMattsonJBashamBSedgwickJD, and others. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med201:233–40.
62.
LaywellEDRakicPKukekovVGHollandECSteindlerDA. 2000. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A97:13883–8.
63.
MacasJNernCPlateKHMommaS. 2006. Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. J Neurosci26:13114–9.
64.
MagnussonJPGoritzCTatarishviliJDiasDOSmithEMLindvallO, and others. 2014. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science346:237–41.
65.
MeletisKBarnabe-HeiderFCarlenMEvergrenETomilinNShupliakovO, and others. 2008. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol6(7):e182.
66.
MiraHAndreuZSuhHLieDCJessbergerSConsiglioA, and others. 2010. Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell7:78–89.
67.
MoalemGLeibowitz-AmitRYolesEMorFCohenIRSchwartzM. 1999. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med5:49–55.
MoriyamaMFukuharaTBritschgiMHeYNarasimhanRVilledaS, and others. 2011. Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis. J Neurosci31:3981–9.
71.
MosmannTRCherwinskiHBondMWGiedlinMACoffmanRL. 1986. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol136:2348–57.
72.
MotheAJTatorCH. 2013. Review of transplantation of neural stem/progenitor cells for spinal cord injury. Int J Dev Neurosci31:701–13.
73.
MuYGageFH. 2011. Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener6:85.
74.
Nait-OumesmarBPicard-RieraNKerninonCDeckerLSeilheanDHoglingerGU, and others. 2007. Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci U S A104:4694–9.
75.
OkadaSNakamuraMMikamiYShimazakiTMiharaMOhsugiY, and others. 2004. Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res76:265–76.
76.
OrtegaSBNoorbhaiIPoinsatteKKongXAndersonAMonsonNL, and others. 2015. Stroke induces a rapid adaptive autoimmune response to novel neuronal antigens. Discov Med19:381–92.
77.
OurednikJOurednikVLynchWPSchachnerMSnyderEY. 2002. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol20:1103–10.
78.
PackerMAStasivYBenraissAChmielnickiEGrinbergAWestphalH, and others. 2003. Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci U S A100:9566–71.
ParkHLiZYangXOChangSHNurievaRWangYH, and others. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol6:1133–41.
81.
Pérez EstradaCCovacuRSankavaramSRSvenssonMBrundinL. 2014. Oxidative stress increases neurogenesis and oligodendrogenesis in adult neural progenitor cells. Stem Cells Dev23:2311–27.
82.
PetitASandersADKennedyTETetzlaffWGlattfelderKJDalleyRA, and others. 2011. Adult spinal cord radial glia display a unique progenitor phenotype. PLoS One6(9):e24538.
83.
PfenningerCVSteinhoffCHertwigFNuberUA. 2011. Prospectively isolated CD133/CD24-positive ependymal cells from the adult spinal cord and lateral ventricle wall differ in their long-term in vitro self-renewal and in vivo gene expression. Glia59:68–81.
84.
Picard-RieraNDeckerLDelarasseCGoudeKNait-OumesmarBLiblauR, and others. 2002. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A99:13211–6.
85.
PiersonESimmonsSBCastelliLGovermanJM. 2012. Mechanisms regulating regional localization of inflammation during CNS autoimmunity. Immunol Rev248:205–15.
86.
PluchinoSMuzioLImitolaJDeleidiMAlfaro-CervelloCSalaniG, and others. 2008. Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain131(Pt 10):2564–78.
87.
PluchinoSZanottiLRossiBBrambillaEOttoboniLSalaniG, and others. 2005. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature436:266–71.
88.
PrassKMeiselCHoflichCBraunJHalleEWolfT, and others. 2003. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med198:725–36.
89.
RadomskiWMMartinJFMoncadaS. 1991. Synthesis of nitric oxide by the haemocytes of the American horseshoe crab (Limulus polyphemus). Philos Trans R Soc Lond B Biol Sci334:129–33.
90.
RasmussenSImitolaJAyuso-SacidoAWangYStarossomSCKivisakkP, and others. 2011. Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol69:878–91.
91.
ShibuyaSMiyamotoOItanoTMoriSNorimatsuH. 2003. Temporal progressive antigen expression in radial glia after contusive spinal cord injury in adult rats. Glia42:172–83.
92.
ShihabuddinLSHornerPJRayJGageFH. 2000. Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J Neurosci20:8727–35.
93.
SimonATanakaEM. 2013. Limb regeneration. Wiley interdisciplinary reviews. Dev Biol2:291–300.
94.
SpaldingKLBergmannOAlkassKBernardSSalehpourMHuttnerHB, and others. 2013. Dynamics of hippocampal neurogenesis in adult humans. Cell153:1219–27.
95.
SubramanianSZhangBKosakaYBurrowsGGGrafeMRVandenbarkAA, and others. 2009. Recombinant T cell receptor ligand treats experimental stroke. Stroke40:2539–45.
96.
SunD. 2015. Endogenous neurogenic cell response in the mature mammalian brain following traumatic injury. Exp Neurol. EpubApril30. doi:10.1016/j.expneurol.2015.04.017.
97.
TepavcevicVLazariniFAlfaro-CervelloCKerninonCYoshikawaKGarcia-VerdugoJM, and others. 2011. Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis. J Clin Invest121:4722–34.
98.
ThoredPArvidssonACacciEAhleniusHKallurTDarsaliaV, and others. 2006. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells24:739–47.
99.
TobinMKBondsJAMinshallRDPelligrinoDATestaiFDLazarovO. 2014. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab34:1573–84.
100.
TonchevABYamashimaTZhaoLOkanoHJOkanoH. 2003. Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol Cell Neurosci23:292–301.
101.
TrappBDBoLMorkSChangA. 1999. Pathogenesis of tissue injury in MS lesions. J Neuroimmunol98:49–56.
102.
ValerioAFerrarioMDreanoMGarottaGSpanoPPizziM. 2002. Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells. Mol Cell Neurosci21:602–15.
103.
VallieresLCampbellILGageFHSawchenkoPE. 2002. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci22:486–92.
104.
van PraagHKempermannGGageFH. 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci2:266–70.
105.
VargheseMOlstornHBerg-JohnsenJMoeMCMurrellWLangmoenIA. 2009. Isolation of human multipotent neural progenitors from adult filum terminale. Stem Cells Dev18:603–13.
106.
VogelgesangADresselA. 2011. Immunological consequences of ischemic stroke: immunosuppression and autoimmunity. J Neuroimmunol231:105–10.
WangYImitolaJRasmussenSO’ConnorKCKhourySJ. 2008. Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol64:417–27.
109.
WeissSDunneCHewsonJWohlCWheatleyMPetersonAC, and others. 1996. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci16:7599–609.
110.
WideraDMikenbergIElversMKaltschmidtCKaltschmidtB. 2006. Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-κB signaling. BMC Neurosci7:64.
111.
WongGGoldshmitYTurnleyAM. 2004. Interferon-γ but not TNF-α promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp Neurol187:171–7.
112.
WuJKuoJLiuYTzengS. 2000. Tumor necrosis factor-α modulates the proliferation of neural progenitors in the subventricular/ventricular zone of adult rat brain. Neurosci Lett292:203–6.
113.
YilmazGArumugamTVStokesKYGrangerDN. 2006. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation113:2105–12.
114.
ZahirTChenYFMacDonaldJFLeipzigNTatorCHShoichetMS. 2009. Neural stem/progenitor cells differentiate in vitro to neurons by the combined action of dibutyryl cAMP and interferon-γ. Stem Cells Dev18:1423–32.
