mending the broken brain: neuroimmune interactions in neurogenesis

*Laboratorio de Neuroinflamacion, Unidad de Neurologıa Experimental, Hospital Nacional de

Paraplejicos-SESCAM, Finca La Peraleda, Toledo, Spain

�Department of Life Sciences, Roehampton University, Whitelands College, London, UK

It has long been accepted that our brains are incapable ofregeneration and as such, from soon after birth neurodegen-eration represents simply a long downward spiral towardssenility. However, recent studies have established that adultmammalian brains maintain some discrete regions of neuro-genesis that are capable of generating functional neurons, eventhough the mechanisms that control this process are poorlyunderstood (Kriegstein and Alvarez-Buylla 2009). It wasrecently demonstrated that in neurodegenerative diseases adultneurogenesis may be substantially augmented (Kempermannet al. 2004; Lie et al. 2004). However, despite the mobiliza-tion of neural progenitors, this response is insufficient topromote full brain repair and recovery. In addition, it has beensuggested that directed differentiation of endogenous neuralprogenitor cells is a mechanism by which neuroadaptation,regeneration, plasticity and brain homeostasis are maintainedon a daily basis (Lledo et al. 2006; Taupin 2006).

Received March 5, 2010; revised manuscript received May 5, 2010;accepted June 2, 2010.Address correspondence and reprint requests to Francisco Molina-

Holgado, Department of Life Sciences, Roehampton University, LondonSW154JD, UK, E-mail: [email protected] orEduardo Molina-Holgado, Laboratorio de Neuroinflamacion, Unidad deNeurologıa Experimental, Hospital Nacional de Paraplejicos-SESCAM,Finca La Peraleda, s/n 45071 Toledo, Spain.E-mail: [email protected] used: 2-AG, 2-arachidonoyl glycerol; AD, Alzheimer’s

disease; ADAM, a-disintegrin and metalloproteinase; CB, cannabinoid;CI, cerebral ischaemia; DAG, diacylglycerol; DAGL, diacylglycerollipase; EAE, experimental autoimmune encephalomyelitis; IFN, inter-feron; IGF-I, insulin-like growth factor-1; IL, interleukin; LPS, lipopo-lysaccharide; MHC, major histocompatibility complex; NSC, neuralstem/progenitor cells; PD, Parkinson’s disease; SGZ, subgranular zone;sIL-6R, soluble IL-6 receptor; SVZ, subventricular zone; TACE, TNF-aconverting enzyme; TLR, toll-like receptor; TNF-a, tumor necrosisfactor alpha.

Abstract

Neuroimmune networks and the brain endocannabinoid sys-

tem contribute to the maintenance of neurogenesis. Cytokines

and chemokines are important neuroinflammatory mediators

that are involved in the pathological processes resulting from

brain trauma, ischemia and chronic neurodegenerative dis-

eases. However, they are also involved in brain repair and

recovery. Compelling evidence obtained, in vivo and in vitro,

establish a dynamic interplay between the endocannabinoid

system, the immune system and neural stem/progenitor cells

(NSC) in order to promote brain self-repair. Cross-talk between

inflammatory mediators and NSC might have important con-

sequences for neural development and brain repair. In addition,

brain immune cells (microglia) support NSC renewal, migration

and lineage specification. The proliferation and differentiation of

multipotent NSC must be precisely controlled during the

development of the CNS, as well as for adult brain repair. Al-

though signalling through neuroimmune networks has been

implicated in many aspects of neural development, how it

affects NSC remains unclear. However, recent findings have

clearly demonstrated that there is bi-directional cross-talk

between NSC, and the neuroimmune network to control the

signals involved in self-renewal and differentiation of NSC.

Specifically, there is evidence emerging that neuroimmune

interactions control the generation of new functional neurones

from adult NSC. Here, we review the evidence that neuro-

immune networks contribute to neurogenesis, focusing on the

regulatory mechanisms that favour the immune system

(immune cells and immune molecules) as a novel element in the

coordination of the self-renewal, migration and differentiation of

NSC in the CNS. In conjunction, these data suggest a novel

mode of action for the immune system in neurogenesis that may

be of therapeutic interest in the emerging field of brain repair.

Keywords: brain repair, endocannabinoid system, microglia,

neurodegenerative diseases, neurogenesis, neuroimmune

interactions, neuroinflammation.

J. Neurochem. (2010) 114, 1277–1290.

JOURNAL OF NEUROCHEMISTRY | 2010 | 114 | 1277–1290 doi: 10.1111/j.1471-4159.2010.06849.x

� 2010 The AuthorsJournal Compilation � 2010 International Society for Neurochemistry, J. Neurochem. (2010) 114, 1277–1290 1277

Embryonic/adult neurogenesis is currently one of the mostexciting issues in neuroscience, although the lack ofinformation about the processes involved has made itdifficult to comprehend why neurogenesis sometimes failsto produce new neurons. Accordingly, it has so far provedimpossible to identify the missing factors that would form thebasis for both the induction and implantation of cell-basedtherapies. Such therapies could be beneficial to treat/reverseall manner of neurodegenerative diseases, as well asproviding an important insight as to how the brain functions(Lindvall and Kokaia 2010).

The evidence that is accumulating suggests that there is asynergy between the immune system and neural stem/progenitor cells (NSC) to promote functional recovery, asimmune cells help to maintain neurogenesis in germinalcentres of the adult CNS even under non-pathologicalconditions (Butovsky et al. 2006; Ziv et al. 2006a,b; Ekdahlet al. 2009; Mathieu et al. 2010). Similarly, there issubstantial evidence that NSC proliferation in the subventric-ular zone (SVZ) of the lateral ventricles is altered in variousneurodegenerative diseases (Curtis et al. 2007). Therefore,some cross-talk between elements involved in the neuroin-flammatory response and those that interact with NSC mightoccur, which to some extent may activate endogenous brainrepair (Curtis et al. 2007; Rolls et al. 2007).

In this context, understanding when, where and howneuroimmune signalling mechanisms regulate the NSClineage may help us better understand the interactions ofcytokines and chemokines with the elements in the brain thatregulate CNS development, neuroprotection and repair. Inaddition, such information may help to define new strategiesto amplify these restorative CNS responses in order tostimulate brain repair and hence, to reverse nerve damage inneurodegenerative diseases.

There are many excellent reviews that have recentlydiscussed specific aspects of CNS immune mediators, and ofNSC regulation and function in considerable depth (Boulan-ger 2009; Carpentier and Palmer 2009; Deverman andPatterson 2009; Mathieu et al. 2010). Thus, in order not tocover the same ground, we rather aim to present an overviewof the key features of neuroimmune interactions in neuro-genesis, highlighting some mechanisms that may be commonto what would otherwise seem to be diverse CNS neurode-generative disorders. In addition, we shall discuss thelimitations of current approaches and the major gaps in ourpresent knowledge, as well as focusing on the implicationsand applications of recent discoveries regarding the regen-erative function of the brain endocannabinoid system as aninterface between the CNS and the immune system (Fig. 1).

The brain as an immune organ, an emerging concept

The brain response to inflammatory insults such as tissueinjury, degenerative disease or infection differs from that in

peripheral tissues as it does not involve a classical immuneresponse. This is because of the presence of the blood brainbarrier, which limits molecular/cellular trafficking into thebrain, as well as to the absence of a lymphatic system for thecells to migrate through, the low expression of the majorhistocompatibility complexes (MHC-I and MHC-II) and thepoor antigen presenting ability of local microglia (Rivest2009). Hence, the brain is considered as an ‘immuneprivileged’ organ (Allan and Rothwell 2003; Bechmannet al. 2007), as it is a sensitive organ with poor regenerativecapacity that lacks elements indispensable for damagelimitation during inflammation (Galea et al. 2007). However,this view of the brain as an ‘immune privileged’ site haschanged dramatically over the last decade as the result ofresearch into the interactions between the brain and theimmune system, the CNS now being considered as animmune organ (Schwartz 2010).

Evidence is accumulating to suggest that the interactionbetween the CNS and the immune system relies on the

Fig. 1 The emerging functions of endocannabinoid signalling in neu-

rogenesis. Schematic model of the downstream neurogenic effects of

the endocannabinoid system in the CNS. Endogenous or exogenous

cannabinoid agonists interact with the CB1 and CB2 cannabinoid

receptors, or with GPR55, the ‘third’ cannabinoid receptor, modulating

neural stem cell (NSC) self-renewal or NSC fate specification through

diverse downstream neurogenic pathways and immune system mod-

ulators.

1278 | E. Molina-Holgado and F. Molina-Holgado

Journal Compilation � 2010 International Society for Neurochemistry, J. Neurochem. (2010) 114, 1277–1290� 2010 The Authors

expression of several cytokines, chemokines and theirreceptors in both neurons and glial cells in the brain. Thisconcept is consistent with the existence of an immune systemin the brain and opens the possibility of true cross-talkbetween the nervous and immune systems (Mueller et al.2005). In support of these findings, new data regarding themajor histocompatibility complex in CNS neurons haveestablished a surprising role for MHC-I in neuronal plasticityand the fine tuning of neural circuits (Shatz 2009). Thesefindings are in contrast to a recent study performed infunctional MHC-I knockout mice, transporter associated withantigen processing 1 KO, that do not support a role for MHCclass I in adult neurogenesis, although it may still have a rolein the maturation and integration of newborn neurons(Laguna Goya et al. 2010). Interestingly, it is also knownthat exogenous cytokines such as tumor necrosis factor alpha(TNF-a) can alter MHC expression/plasticity related activ-ities (Bhat and Steinman 2009). More importantly, primaryNSC can establish immunological synapses with T cells andmore specifically, purified CD8+ T cells proliferate tostimulate NSC and this proliferation is blocked by MHCclass I (Imitola et al. 2004a).

In terms of phylogenetic/evolutionary development, thenervous system’s increasing complexity is associated with agradual loss of its regenerative response, a consequence of itsinnate immunity as well as the evolutionary development ofadaptative immunity (Popovich and Longbrake 2008). Both,the innate immune response (stimulated by cell death, braininjury or infection) and the adaptative immune response inthe brain [mainly activated by the cytokines IL-1b, IL-6,TNF-a or interferon (IFN)-c] are susceptible to endogenousregulation by the hypothalamic-pituitary-adrenal axis, lym-phocytes, macroglia, microglia and neurones (Carpentierand Palmer 2009). Thus, the balance between detrimentalinflammation versus protective inflammation will have aprofound impact on the efficiency of brain repair (Martino2004). Some of the discrepancies between studies and thedifficulties of interpretation may be explained by the patternof change with neurodegeneration severity or the modelssystem used. Interpretation becomes even more complicatedfor studies utilizing peripheral (blood) and CSF samples, aschanges may not reflect what is happening in the brain andthere is a scarcity of studies examining the status ofneuroinflammatory mediators targeting specific brain regionsaffected by a particular neurodegenerative process. Despitethe controversies in the field, this dichotomous neuroinflam-matory scenario will ultimately be managed to harness CNSrepair.

Contribution of signalling from the innate andadaptative immune system to neurogenesis

Microglial cells, myeloid cells derived from bone marrow,are present in the CNS and they constitute the first

immunological barrier against pathogens and environmentalinsults (Hanisch and Kettenmann 2007). An innate immuneresponse involving microglial cells occurs after CNSinfection, but also during brain injury or chronic disease(Rivest 2009). In addition, marked recruitment, proliferationand activation of microglial cell precursors from the bloodcan be detected in damaged regions of the brain (Soulet andRivest 2008). Microglia, astrocytes and endothelial cells areinvolved in the intracerebral immune response where theyact, in part, by secreting cytokines, chemokines, neurotroph-ic or neurotoxic factors (Bailey et al. 2006). For example, inresponse to neuroinflammation, activated microglial cellsmigrate toward dying neurons and they exacerbate local celldamage (Streit et al. 2005). In addition to their role inphagocytosis, activated microglia are also classified asantigen presenting cells as they up-regulate MHC-II. Indeed,resident microglial cells, infiltrating macrophage and/ordendritic cells can process and present myelin epitopes, inassociation with MHC-II molecules, to CD4+ T cells withinthe CNS of Theiler’s virus-infected mice (Katz-Levy et al.1999) and in experimental autoimmune encephalomyelitis(EAE), established models of multiple sclerosis. Yet, in EAErecent data suggest that naive T cells enter the inflamed CNSand are activated by local antigen-presenting cells, possiblydendritic cells, to endogenous myelin epitopes to initiateepitope spreading (McMahon et al. 2005).

Initial studies provided evidence that acute activation oflocal or systemic innate proinflammatory cascades has aprofound negative effect on postnatal and adult neurogen-esis. Two pioneering reports showed that lipopolysaccharide(LPS) infused into the brain caused widespread microglialand astroglial activation, strongly suppressing neurogenesisin the adult rodent hippocampus (Ekdahl et al. 2003; Monjeet al. 2003). LPS activation of toll-like receptor (TLR) 4 inmicroglial cells is associated with a proinflammatoryphenotype, and cells release interleukin-1b (IL-1b), TNF-a and IL-6, among other effectors (Laflamme et al. 2003;Taylor et al. 2010). Co-culture of hippocampal NSC withactivated but not resting microglia decreases immaturedoublecortin (DCX)-expressing neurons and similarly,exposure of NSC to recombinant IL-6 or TNF-a decreasesin vitro neurogenesis (Monje et al. 2003; Cacci et al. 2005).Transgenic mice that chronically over-express IL-6 underthe glial fibrilliary acidic protein (GFAP) promoter alsoexhibit reduced adult hippocampal neurogenesis (Valliereset al. 2002). Likewise, signalling through TNF-R1 sup-presses neural progenitor proliferation and neurogenesis inthe adult brain in vivo, whereas cell proliferation in thesubgranular zone (SGZ) of the dentate gyrus is elevated inthe TNFR1KO mouse under both basal conditions and whenneurogenesis was stimulated by an epileptic insult (Iosifet al. 2006). From these studies, it is clear that a majorproblem limiting endogenous neurogenesis after braininsults is the poor survival of newly generated neurons as

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� 2010 The AuthorsJournal Compilation � 2010 International Society for Neurochemistry, J. Neurochem. (2010) 114, 1277–1290

a result of a hostile environment involving proinflammatorymicroglia.

However, under certain conditions following brain inflam-mation or injury, activated microglia are permissive to brainrepair, providing neuroprotection (Carson et al. 2006) oracting as a proneurogenic influence that supports thedifferent steps of neurogenesis (Ekdahl et al. 2009; Thoredet al. 2009). In an elegant study Byram and colleaguesdemonstrated that following facial motoneuron axotomy, thegeneration of neuroprotective CD4+ T-cell responses wasfound to depend on antigen presentation by both peripheralantigen presenting cells (APCs) and CNS-resident microglia(Byram et al. 2004). A beneficial role of microglia in adultneurogenesis is evident through in vitro studies on SVZ NSCco-cultured with microglia, the latter secreting factors topromote the differentiation of neurogenic astrocytes intoneurons (Walton et al. 2006). Other experiments indicate thatneurogenesis and oligodendrogenesis is induced by microgliathat encounter well-controlled levels of T-helper cytokines,IL-4 and low levels of IFN-c, associated with adaptiveimmunity (Butovsky et al. 2006). Microglia primed with IL-4 strongly express MHC-II and the potent proneurogenicinsulin-like growth factor-1 (IGF-I) (Butovsky et al. 2005).An interesting parallel occurs in the dentate gyrus of ratsexposed to an enriched environment. In this experimentalmodel, CNS-specific autoimmune T-lymphocytes interactwith resident microglia to promote neurogenesis in the SGZand possibly, to influence neuronal differentiation (Ziv et al.2006a). Interestingly, in experimental antigen-induced arthri-tis, a model of peripheral adaptative immune response thatlacks an inflammatory central phenotype, a significantincrease in the numbers of DCX-positive precursor cells isparalleled by an increase in corticosterone levels in thehippocampus (Wolf et al. 2009). These data indicate thatCNS-specific T cells exert a neurogenic effect.

Although the inflammatory environment clearly influencesseveral aspects of adult neurogenesis, NSC themselves alsoexpress immune-relevant molecules. TLRs, cell-adhesionmolecules, cytokines and chemokine receptors, and MHC-Ienable NSC to functionally interact with an inflamed CNSmicroenvironment (Martino and Pluchino 2007; Rolls et al.2007). Indeed, NSC express TLR2 and TLR4 and thesereceptors are involved in cell proliferation and differentia-tion (Rolls et al. 2007). This suggests that TLR activationon NSC regulates neurogenesis in response to injury andinflammation. In vitro, TLR2 activation with pharmacolog-ical activators promotes neuronal differentiation although itdoes not affect self-renewal. Conversely, inhibition of TLR2signalling impairs neuronal differentiation, in parallel withan increase in glial differentiation. TLR4 seems to havedistinct effects as its activation inhibits both neuronaldifferentiation and self-renewal of NSC (Rolls et al. 2007).In conclusion, microglia activation is a dynamic andmultifaceted process responding to instructive signal from

the microenvironment that ultimately determine its neuro-genic potential.

Immune cells/molecules support neurogenesis

At present, the precise role of immune cells and inflamma-tory mediators in CNS repair and recovery is unknown,although several experimental studies in vivo and in vitroimply beneficial effects of specific inflammatory mediators inrepair, regulation and recovery. This is a key area of researchin NSC biology, attracting the attention of several researchgroups trying to identify positive and negative immuneregulators expressed by cells in the brain that can modulateneural stem/progenitor cell self-renewal and cell fate spec-ification in order to enhance brain repair. Two scenarios havebeen proposed to explain how neuroimmune processes coulddetermine NSC behaviour. While neuroinflammation couldgenerate an environment detrimental for repair, alternativelyit could also create an environment permissive for neuro-repair (Mueller et al. 2005), and it is most likely that thebalance between these possibilities determines the eventualoutcome. Current evidence shows that the cytokines IL-1,IL-6 and TNF-a play a role in complex restorative processesat the molecular level, such as synaptic plasticity andneurogenesis, as well as in neuromodulation (Barkho et al.2006; Rubio-Araiz et al. 2008; McAfoose and Baune 2009).

Interleukin-1 signalling in neurogenesisIn recent years, there has been much debate about thecontribution of IL-1 to ‘physiological’ responses in the CNSin the absence of disease or injury (Allan and Rothwell2003). The IL-1 family fulfils an important role in inflam-mation and host defence, and it is regulated at many levels(Allan et al. 2005). However, IL-1 can also exert beneficialeffects, particularly when released in modest concentrations.IL-1b can enhance the survival of primary neurons in vitro,either by direct or indirect induction of nerve growth factorrelease from astrocytes (Spranger et al. 1990; Brennemanet al. 1992), as well as enhance the expression of p75neurotrophin receptor (Moser et al. 2004). Moreover, IL-1bcontributes to long term potentiation (Schneider et al. 1998).IL-1b also induces the production of fibroblast growth factor-2, which can act as a trophic factor for motor or forebrainneurons (Ho and Blum 1997; Albrecht et al. 2002). Inaddition, IL-1 is involved in the differentiation of oligoden-drocyte progenitors and it supports the maturation andsurvival of differentiated cells (Vela et al. 2002). Such a roleindicates that IL-1 might affect myelination processes andindeed, IL-1b-deficient mice experience a delay in remyeli-nation, which is indicative of a role in some repair processesin the CNS (Mason et al. 2001). Although IL-1 has beenattributed a variety of effects on distinct cell types, themechanisms underlying such actions are not fully under-stood.



During CNS development, IL-1b could participate in theregulation of neuronal proliferation in diverse brain regions.In this regard, IL-1b influences proliferation and earlydifferentiation during spinal cord development in chickembryos (De la Mano et al. 2007). Moreover, IL-1bstimulates the in vitro differentiation of neural progenitorsto dopaminergic neurons in both rodents and humans byactivating the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway (Wang et al. 2007)and hypoxia inducible factor 1a (Kim et al. 2008). IL-1balso induces neuronal differentiation in cultures of humanneuroepithelial olfactory cells (Vawter et al. 1996). How-ever, the precise mechanism involved in these eventsremains to be elucidated. In addition to the role of IL-1brole in cell fate specification, the other member of the IL-1family, IL-1a augments the expression of genes associatedwith neurogenesis during neuronal induction. Indeed, IL-1aenhances neurogenesis in human adult mesenchymal stemcells (Greco and Rameshwar 2007). However, there is recentevidence that IL-1b may also inhibit neurogenesis (Koo andDuman 2008). Acute stress decreases NSC proliferation andthat this effect is mediated by IL-1b/nuclear factor kappaB(NF-jB) signalling (Koo et al. 2010). Furthermore, IL-1signalling and the resulting glucocorticoid secretion medi-ates the development of depressive symptoms associatedwith exposure to acute and chronic stress, at least partly viasuppression of hippocampal neurogenesis (Goshen andYirmiya 2009). In contrast, treatment with antidepressantsincreases neurogenesis by inducing NSC proliferation(Malberg et al. 2000). Because the expression of the IL-1receptor antagonist (IL-1ra) is known to increase concom-itantly with IL-1 (Dinarello 1996), modulation of neurogen-esis by IL-1ra has been examined in a transgenic mouseover-expressing the IL-1ra in the brain-directed (Tg hsIL-1ra), blocking IL-1 receptor-mediated activity abolished thealterations to neurogenesis after acute and chronic neuroin-flammation (Spulber et al. 2008). Furthermore, intrahippo-campal transplantation of transgenic neural precursor cellsover-expressing IL-1ra blocks chronic isolation-inducedimpairment of memory and neurogenesis (Ben Menachem-Zidon et al. 2008). Overall, the precise mechanisms under-lying the influence of IL-1 on proliferation or lineagespecification still remain to be fully elucidated.

Interleukin-6 signalling in neurogenesisInterleukin-6 is a pleiotropic cytokine involved in theregulation of inflammatory and immunological responses,acute phase protein production, and hematopoiesis, whichsignals through the gp130 receptor family. Although initiallyconsidered to be a pro-inflammatory cytokine, IL-6 alsoappears to have many anti-inflammatory and immunosup-pressive effects (Tilg et al. 1997). In glial cells challengedwith IFNc/IL-1b and IFNc/LPS, IL-6 inhibits the release ofTNF-a (Shrikant et al. 1995). Moreover, in a viral model of

multiple sclerosis IL-6 suppresses demyelination (Rodriguezet al. 1994), whereas increased IL-6 mRNA expression inblood and cerebrospinal fluid has been described in patientswith multiple sclerosis (Navikas et al. 1996).

There is increasing evidence supporting a role for the IL-6receptor family in CNS development, as well as duringneurodegeneration and regeneration (Gadient and Otten1997). Interleukin-6 promotes differentiation of NSC toneuronal lineages at relatively low concentrations throughthe Janus kinase (JAK)/STAT (signal transducers andactivators of transcription protein) pathway (Barkho et al.2006), a finding that contrasts with the common assumptionthat inflammatory cytokines only inhibit neuronal differen-tiation of NSC (Monje et al. 2003). IL-6 regulates thedifferentiation of neuronal precursor cells both in theperipheral nervous system and in the spinal cord, as wellas the survival of differentiated neurons and the differenti-ation of astrocytes and oligodendrocytes (Kahn and De Vellis1994; Murphy et al. 1997).

Consistent with previous findings, a highly active IL-6fusion protein (Hyper-IL-6 – H-IL-6) and the soluble IL-6receptor (sIL-6R) induce NSC to differentiate specificallyinto glutamate-responsive neurons, oligodendrocytes, andphenotypically distinct glia, an effect that is stronglydependent on sIL-6R (Islam et al. 2009). In addition, anIL-6R/IL-6 chimera (sIL-6R fused to interleukin-6) greatlyimproves the myelinating capacity of embryonic stem cell-derived NSC (Zhang et al. 2006). Other studies haveimplicated the MAPK/cAMP response element-bindingprotein cascade in H-IL-6–activated neurogenesis, whereasgliogenesis is mediated via STAT-3 (signal transducers andactivators of transcription protein-3) signalling (Islam et al.2009). By contrast, IL-6 release by activated microglia hasbeen identified as a key inhibitor of neurogenesis inmicroglial conditioned medium (Monje et al. 2003). Expo-sure to recombinant IL-6 decreased neurogenesis in vitro byapproximately 50%, and the addition of neutralizing anti-IL-6 antibodies to conditioned medium from activated microgliafully restored in vitro neurogenesis (Monje et al. 2003).

Like many cytokines, IL-6 may have distinct physiologicaleffects at different concentrations and in different biologicalcontexts (Bauer 2009). The apparent inconsistency in theproneurogenic or anti-neurogenic effects of IL-6 could reflectdifferences in the amounts and conditions used experimen-tally. Indeed, the effects of IL-6 might also vary in functionof the length of exposure duration, suggesting that areprobably context and concentration dependent.

Tumour necrosis factor signalling in neurogenesisIn addition to its well established function as a proinflam-matory cytokine, TNF-a now also appears to play animportant role in neural plasticity and neurorepair (Oshimaet al. 2009; Wheeler et al. 2009; Rainey-Smith et al. 2010).TNF-a is involved in the pathogenesis of several acute and



chronic neurodegenerative disorders (Allan and Rothwell2003). For example, TNF-a is detrimental to neurons after astroke but it also contributes to the repair process, as infusionof anti-TNF-a antibodies reduce the survival of newlyformed neuroblasts (Heldmann et al. 2005). Thus, the actionof TNF-a is complex and depends on the target cells andreceptors engaged. Recent efforts to disentangle these twoopposing actions of TNF-a have focused on the specificreceptors it activates. TNF-a acts through two differentreceptor subtypes, TNF-RI and TNF-RII (Allan and Rothwell2003), and evidence from TNF-a receptor knock-out micesuggests that signalling through TNF-RI suppresses neuralprogenitor proliferation and neurogenesis in vivo, whilstsignalling through TNF-RII enhances neurogenesis underbasal conditions or in neurodegenerative disorders (Iosifet al. 2006).

Through the activation of the I kappa B-kinase (IKK)/NF-jB signalling pathway, prolonged exposure to TNF-apromotes proliferation of adult NSC in culture (Widera et al.2006). Furthermore, an endogenous pool of TNF-a is criticalto promote self-renewal of NSC as proliferation is abolishedwhen cultures maintained in the presence of fibroblastgrowth factor/epidermal growth factor are exposed to aspecific anti-TNF-a blocking antibody (Rubio-Araiz et al.2008). In experimental models of demyelination, TNF-asignalling through TNF-RII promotes the accumulation ofproliferating oligodendrocyte progenitors, which differentiateinto mature oligodendrocytes (Arnett et al. 2001). Exposureof human NSC to proinflammatory cytokines increasesoligodendrocyte generation following serum-induced differ-entiation, suggesting that multipotent NSC may increase theirmyelinotrophic activity during inflammation (Ricci-Vitianiet al. 2007). Accordingly, NSC produce TNF-a in response toTLR2 and TLR4 agonists, proving the functionality of thesereceptors under inflammatory conditions (Covacu et al.2009). Indeed, TNF-a is also proposed to act as a mitogenwhen injected into the subventricular zone (Wu et al. 2000;Liu et al. 2005), a region giving rise to new oligodendrocyteprecursors in the lesioned adult brain (Menn et al. 2006).

Tumor necrosis factor-RI inhibition could provide apossible therapeutic approach to potentiate the positive roleof TNF-a in the remyelination of damaged axons. TNF-RIand TNF-RII exist as preformed trimers that facilitate thebinding of the TNF trimer, while the N-terminal cysteine richdomains hold the trimer together (MacEwan 2002). One wayof disrupting TNF-a receptor signalling is to disrupt thistrimer (Deng et al. 2005; Chan 2007), providing an oppor-tunity to develop selective therapeutic TNF-RII agonists orTNF-RI inhibitors. Other evidence confirmed that the activityof the TNF-a converting enzyme TACE/ADAM17 (thatplays an essential role in shedding ectodomains from avariety of proteins such as TNF-alpha) induces neuralprogenitor proliferation in the SVZ under pathologicalconditions. Indeed, intra-cerebroventricular infusion of a

TNF-a protease inhibitor-2, TAPI-2 (a TACE/ADAM17inhibitor), decreases NSC proliferation in the same region(Katakowski et al. 2007). Consequently, it is clear that TNF-asignalling may influence the ability of NSC to repair localdamage in the brain.

Brain self-repair in neurodegeneration

It now appears that there is some synergy between theimmune system and NSC to promote functional recovery, asimmune cells help to maintain neurogenesis in germinalcentres of the adult CNS even under non-pathologicalconditions (Butovsky et al. 2006; Ziv et al. 2006a,b).Similarly, there is considerable evidence that neural stemcell proliferation in the SVZ is modulated in variousneurodegenerative diseases (Curtis et al. 2007). Therefore,some cross-talk between elements involved in the neuroin-flammatory response and those that interact with NSC mightoccur and to some extent, may activate endogenous brainrepair (Rolls et al. 2007).

The SVZ is differentially activated by various neurode-generative pathologies. In response to neurodegenerationfollowing stroke, brain injury, vascular dementia, Hunting-ton’s disease, multiple sclerosis or epilepsy, there is an up-regulation of the cytokines produced and an increase inendogenous neurogenesis that augments the number of PSA-neural cell adhesion molecule (NCAM)-positive NSC closeto the lateral ventricular walls (Macas et al. 2006; Curtiset al. 2007, Minger et al. 2007; Nait-Oumesmar et al. 2008;Ekonomou et al. 2010). More importantly, this capacity isretained even in old age (Macas et al. 2006; Minger et al.2007). By contrast in Parkinson’s disease (PD) and Alzhei-mer’s disease (AD) there are fewer proliferating cells in theSVZ.

StrokeThere is experimental evidence that global and focalischaemia activates neural progenitor proliferation andmigration in the damaged area (Curtis et al. 2007). Newneurones may be generated in the cerebral cortex aftercerebral ischaemia in the human brain (Jin et al. 2006),however, it is difficult to unequivocally establish enhancedneurogenesis as the sole factor that improves neurologicalfunction after cerebral ischaemia (CI). It is likely thatbehavioural recovery will result from a combination ofneurogenesis, angiogenesis, neuroprotection and synapticpreservation. Specifically, the long-term accumulation ofmicroglia with the proneurogenic phenotype in the SVZimplies a supportive role of these cells for continuedneurogenesis after stroke (Lindvall and Kokaia 2008; Thoredet al. 2009). Experimental CI stimulates neurogenesis in theSVZ and SGZ, and it promotes the migration of neuroblasts,guided by blood vessels, into the areas of damage (i.e. theperi-infarct cortex and striatum: Ohab and Chamichael



2008). Migration toward the site of injury is the first criticalstep in stem cell engagement during regeneration (Imitolaet al. 2004b). The proliferation, migration, differentiationand integration into the existing neuronal circuit of thesenewly born neurones has been described as a compensatorymechanism to repair the damaged brain after CI in order topromote functional recovery (Zhang et al. 2006). The signalsthat stimulate post-CI neurogenesis within the SVZ are notfully characterised, although the involvement of numerousgrowth factors and inflammatory mediators has been sug-gested. In particular, stroke-induced SVZ proliferation ispromoted by TNF-a converting enzyme protease activity(Katakowski et al. 2007). Moreover, the treatment of strokewith a nitric oxide donor up-regulates SDF1/CXCR4,angiopoietin 1 and the endothelium-specific tyrosine kinaseTie-2 (Ang1/Tie2) pathways and thus, it probably increasesSVZ neuroblast cell migration and promotes angiogenesis(Cui et al. 2008; Fukuhara et al. 2010). Similarly, thecytokine transforming growth factor alpha has proangiogenicand proneurogenic effects, and it can potentially reduceinfarct volumes and increase neurogenesis in the SVZ (Maet al. 2008; Leker et al. 2009). A number of factors areregulated by iron (Misumi et al. 2008) and it is known thatlipohilic iron chelators can stimulate cell proliferation anddifferentiation (Landschulz et al. 1984), possibly by stabil-ising hypoxia inducible factors and cAMP response element-binding protein (Chu et al. 2008; Siddiq et al. 2009).However, the application of iron chelators as enhancers ofneurogenesis is in very early stages of development andtherefore, more studies are warranted (Williams et al. 2009).

Multiple sclerosisThe SVZ is reactivated in experimental models of demy-elination and in multiple sclerosis in human subjects,increasing NSC or oligodendrocyte progenitor cell prolifer-ation and to some extent inducing oligodendrogenesis(Calza et al. 1998; Picard-Riera et al. 2002; Nait-Oumesmaret al. 2007). Consistently, adult SVZ astrocytes (type Bcells) serve as primary stem cells for new oligodendrocytesin the normal and injured brain (Doetsch 2003; Menn et al.2006), although their mobilization, differentiation andoligodendrocyte replacement remain limited (Nait-Oumes-mar et al. 2008). On the other hand, a significant decrease inthe proliferation of both fast cycling (type C cells) andslowly dividing (type B cells) cells has been described,accompanied by an increase of newly generated non-migratory neuroblasts (type A cells) in the SVZ of EAEmice during the peak of CNS-confined chronic inflammation(Pluchino et al. 2008). These observations suggest that theinflamed brain microenvironment sustains non-cell-autono-mous deregulation of the endogenous CNS stem cellcompartment, a response that may neutralize the mobiliza-tion of endogenous precursors in chronic inflammatory braindisorders (Pluchino et al. 2008).

Previous studies in experimental animal models of EAEattributed a role to microglial cells in both supporting andblocking oligodendrocyte renewal from an endogenous NSCpool (Butovsky et al. 2006). Other studies found that acuteLPS-induced microglial activation prevented the accumula-tion of myelin debris and blocked the premature recruitmentof oligodendrocyte progenitor cells to the border of demye-linated lesions (Glezer et al. 2006). For example, IL-4supported oligodendrogenesis and clinical recovery in animalmodels of transient or chronic EAE. This observation ispartially supported by in vitro findings that IL-4 releasedfrom microglial cells, in part, via the production of IGF-I anddown-regulation of TNF-a, neutralizes the blockage inoligodendrogenesis induced by high-dose of IFN-c (Butov-sky et al. 2006). Moreover, this effect was fully blocked byanti-IGF-I antibodies (Butovsky et al. 2005). Surprisingly, asimilar finding was reported for TNF-a, and the detrimentaleffect of this cytokine might also be dependent on the contextand concentration (Bruce et al. 1996; Frei et al. 1997). TNF-ablockers are efficient to treat autoimmune disorders but theycan induce adverse effects in the CNS, including aggravationof multiple sclerosis (MS) (Hamon et al. 2007). Studies inexperimental models of toxic demyelination with cuprizonehave shown that in mice lacking TNF-a acute demyelinationprogress slow. However, the lack of TNF-a and TNF-RIIleads to a significant reduction in proliferating NG2+

oligodendrocyte progenitors and a delay in the generationof mature oligodendrocytes. Thus, TNF-a signalling throughTNF-RII promotes the proliferation of oligodendrocyteprogenitor cells and the remyelination of damaged axons(Arnett et al. 2001).

Parkinson’s diseaseAlthough the aetiologies of most common forms of PDremain poorly understood, the disease is generally associatedwith an inflammatory component that is partially manifestedby the presence of activated microglia and elevated serumor cerebrospinal fluid levels of pro-inflammatory factorssuch as TNF-a, nitric oxide and IL-1b (Whitton 2007).Activation of microglial TLR4 induces preferential toxicityfor tyrosine hydroxylase-positive neurons and subsequently,the proliferation of new precursors in the neurogenic nichesis inhibited (Saijo et al. 2009). This is consistent with thefindings that dopaminergic receptors are expressed on NSCin the SVZ and regulate their proliferation and differen-tiation (O’Keeffe et al. 2009). Decreased neurogenesisassociated with PD is also evident in experimental modelswhereby reduced olfactory bulb neurogenesis results inimpairing odour discrimination (Lledo et al. 2006).

Alzheimer’s diseaseIn AD, there is an accumulation of amyloid beta dimers,trimers and oligomers that contributes to defects in neuro-genesis and synaptic damage (Crews et al. 2009). The



molecular mechanisms underlying the aberrant neurogenesisin AD are unclear, although several signalling pathways thatcontrol physiological adult neurogenesis are known to bederegulated: Notch, CDK5, Wnt/BMP or Ca2+ influx (Crewset al. 2009). By contrast, several members of the a-disintegrin and metalloproteinase (ADAM) family thatincrease the amount of secreted total amyloid precursorprotein diminish the formation of amyloid beta, and theyhave been associated with proneurogenic events in AD (Yanget al. 2005). ADAMs are particularly important for cleavage-dependent activation of proteins such as Notch, amyloidprecursor protein and transforming growth factor alpha, andthey can bind integrins (Yang et al. 2006). Other evidence,confirms that under pathological conditions or in experimen-tal models of neurogenesis, the activity of the ADAM10,TNF-a-converting enzyme (TACE/ADAM17) or ADAM21or of proteases induces neural progenitor proliferation (Yanget al. 2005; Katakowski et al. 2007; Rubio-Araiz et al.2008).

Interaction of the endocannabinoid andneuroimmune systems in neurogenesis

Over 40 years ago, the discovery of the psychoactiveprinciple of the Cannabis sativa L. plants, D9-tetrahydrocan-nabinol, generated intense research into the physiologicalrole of cannabinoids (Mechoulam et al. 1970). In addition tothe well established behavioral effects of D9-tetrahydrocan-nabinol, it has since been found that synthetic, plant-derivedand endogenous cannabinoids exert profound effects on theCNS. Some of the major findings have been that theendocannabinoid tone and activation of cannabinoid recep-tors modulate inflammatory and immune responses (Kleinand Newton 2007; Cabral and Griffin-Thomas 2009) as wellas reducing CNS damage in models of neurodegeneration(Nagayama et al. 1999; Panikashvili et al. 2001; Marsicanoet al. 2003; Ortega-Gutierrez et al. 2005; Arevalo Martinet al. 2007).

Further research has been made into the specific cannab-inoid CB1 and CB2 receptors, their endogenous ligands, [i.e.arachidonoyl ethanolamide and 2-arachidonoyl glycerol(2-AG)] and the specific enzymatic machinery for theirsynthesis and degradation. This research has revealed theexistence of a whole endocannabinoid system (Di Marzo2008) and that whilst cannabinoid CB1 receptors areabundantly expressed in developing and adult brain (Mail-leux and Vanderhaeghen 1992), the CB2 is predominantlyfound in the immune system where it modulates inflamma-tory processes. CB2 receptors found within the brain aremainly expressed by microglial cells (Cabral and Griffin-Thomas 2009).

Extensive evidence in vivo and in vitro shows a neuro-protective role for the endocannabinoid system in response toneuroinflammation and neurotoxicity. Glial cells are possible

cell targets for immunomodulatory activities of endocanna-binoids, a hypothesis that is supported by the presence of CBreceptors in astrocytes, microglia and oligodendrocytes(Stella 2004). Activating microglial cells causes their prolif-eration rate to increase, phagocytic activity and production ofinflammatory mediators (Oleszak et al. 2004). CB2 receptorsattenuate the generation of different cytotoxic factors whilstimproving the influence of glial cells on neuronal survival(Lastres-Becker et al. 2005). Recent studies indicate thatCB2 receptor expression by encephalitogenic T cells iscritical for controlling inflammation associated with EAE.CB2-deficient T cells in the CNS during EAE exhibitedreduced levels of apoptosis, a higher rate of proliferation andincreased production of inflammatory cytokines, resulting insevere clinical disease (Maresz et al. 2007). An interestinghypothesis to explain how CB2 receptor regulates T-celleffector function in the CNS is that the CB2 receptorbecomes activated once the T cells migrate into the CNS,allowing the CNS to maintain its immunosuppressivemicroenvironment.

The expression of cannabinoid receptors in neurogenicareas of pre- and early postnatal brain suggest the involve-ment of endocannabinoids during development (Berrenderoet al. 1998; Berghuis et al. 2007; Galve-Roperh et al. 2007),axonal growth and guidance (Watson et al. 2008), and adultneurogenesis (Goncalves et al. 2008; Gao et al. 2010).Interestingly, recent data indicate defective neurogenesis incannabinoid CB1 receptor knockout mice (Jin et al. 2006).Cannabinoid CB1 and CB2 receptors are differentiallyexpressed by type B cells and neuroblasts in the SVZ(Arevalo Martin et al. 2007). Endocannabinoid signallingcontrols neural progenitor differentiation in the adult SGZ ofthe hippocampus by promoting astroglial differentiation ofnewly born cells (Aguado et al. 2006).

2-Arachidonoyl glycerol is the most abundant endocann-abinoid in the CNS (Sugiura and Waku 2000) and sn-1diacylglycerol lipases a and b (DAGL a and b) areresponsible for the synthesis of 2-AG from diacylglycerol(DAG: Bisogno et al. 2003; Williams et al. 2003). Notably,DAGLa is expressed in SVZ and in NSC cultures andendocannabinoids are produced by NSC (Molina-Holgadoet al. 2007; Aguado et al. 2006; Goncalves et al. 2008).

Considerable evidence has established that there is adynamic interplay between the endocannabinoid system, theimmune system and neural stem cells (Wolf and Ullrich2008). We presented the first results showing that bi-directional cross-talk between the TNF-a and endocannabi-noid signalling pathways is required to stimulate NSCproliferation (Fig. 2). A transient exposure to exogenousTNF-a promoted NSC proliferation through a mechanismthat apparently involved the production of 2-AG. Inaddition, the proliferative actions mediated by either CB1or CB2 cannabinoid receptors were abolished in thepresence of an anti-TNF-a antibody, suggesting that cann-



abinoids induce the release of TNF-a. Exposure to selectivecannabinoid agonists increases the concentration of TNF-ain NSC cultures (Rubio-Araiz et al. 2008). Moreover, TNF-ainduces a rapid production of DAG by a phosphatidylcho-line-specific phospholipase C (Schutze et al. 1991). Inaddition, we have found new evidence for a cross-talkbetween the IL-1b and the endocannabinoid signallingpathways that is required to stimulate NSC differentiation(Fig. 3). Having generated NSC from mice lacking endog-enous IL-1b (IL-1b knock-out mice), we further confirmedthat IL-1b is essential for NSC differentiation (Author’sunpublished observations). Consistent with these observa-tions are the previous findings that demonstrate that IL-1bstimulate the production of DAG (Rosoff et al. 1988;Schutze et al. 1994), the substrate for the DAGL enzyme.The production of DAG by TNF-a or IL-1b provides an

important clue to understanding the role of the endocann-abinoid system in NSC biology, which is an emerging fieldof research in the regulation of neurogenesis.

Conclusions

A major problem limiting endogenous neurogenesis afterbrain insults is the poor survival of newly generated neuronsas a result of a hostile environment involving proinflamma-tory mediators released by immune cells infiltrating the CNSand the elements of the intracerebral immune response.Initial studies provided evidence that acute activation of localor systemic innate proinflammatory cascades has a profoundnegative effect on postnatal and adult neurogenesis. How-ever, the precise role of immune cells and inflammatorymediators in CNS repair and recovery is not known, although

Fig. 2 Schematic figure showing that acti-

vation of the TNF-a receptors leads to 2-AG

synthesis, which may act on the cells’ own

CB1 and CB2 receptors. Likewise, the

activation of CB1 and CB2 receptors in-

creases TACE expression and thus, the

synthesis of TNF-a from its precursor.

Therefore, the endocannabinoid system

modulates a transient TNF pathway that

induces neural stem cell proliferation. This

work was first published in Rubio-Araiz

et al. 2008 (Reproduced with permission

from Elsevier Inc.).

Fig. 3 Interleukin-1 signalling and its cross-

talk with endocannabinoid signalling modu-

lates neural stem cell differentiation in the

CNS. Activation of IL-1 receptors (IL-1RI/

RII) leads to 2-AG synthesis, which may act

on the cells’ own CB1 and CB2 receptors.

Likewise, the activation of CB1 and CB2

receptors increases IL-1 receptor antago-

nist (IL-1ra) expression, which inhibits the

actions of IL-1b in the CNS. Therefore, the

endocannabinoid system modulates a

transient IL-1 pathway that induces neural

stem cell differentiation.



several experimental studies in vivo and in vitro implybeneficial effects of specific inflammatory mediators inrepair, regulation and recovery. Neuroinflammationcould generate an environment detrimental for repair butalternatively it could also create an environment permissivefor neurorepair, and it is most likely that the balance betweenthese possibilities determines the eventual outcome.

Endocannabinoids appear as new participants connectingthe immune system and neural stem cells. Thus, theendocannabinoid system, which has neuroprotective andimmunomodulatory actions mediated by different signallingcascades in the brain, could assist the process of proliferationand differentiation of embryonic or adult neural stem cells.Embryonic/adult neurogenesis is at present one of the mostexciting phenomena in neuroscience, but lack of understand-ing about how it works has made it difficult to understandwhy neurogenesis fails, and hence identify the missingfactors that would form the basis for both induction andimplantation of cell-based therapies. Such therapies could bebeneficial towards reversing/treating all manner of neuro-degenerative diseases as well as providing an importantinsight as to how the brain functions.

Acknowledgements

EM-H is funded by grants from the Fundacion para InvestigacionSanitaria en Castilla-La Mancha (FISCAM, 2007/19) and Fondo de

Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio

de Ciencia e Innovacion, Spain (04/2120; 08/1999). FM-H is

supported by grants from Roehampton University (UK). We would

like to thank Dr Mark Sefton (BiomedRed) for critical reading of the

manuscript and editorial assistance.

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mending the broken brain: neuroimmune interactions in neurogenesis

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