Metab Brain Dis DOI 10.1007/s11011-014-9523-6

REVIEW ARTICLE

Current perspectives on the link between neuroinflammation and neurogenesis Brian Wang & Kunlin Jin

Received: 2 January 2014 / Accepted: 27 February 2014 # Springer Science+Business Media New York 2014

Abstract The link between neuroinflammation and neurogenesis is an area of intensive research in contemporary neuroscience. The burgeoning amount of evidence accumulated over the past decade has been incredible, and now there remains the figuring out of minutia to give us a more complete picture of what individual, synergistic, and antagonistic events are occurring between neurogenesis and neuroinflammation. An intricate study of the inflammatory microenvironment influenced by the presence of the various inflammatory components like cytokines, chemokines, and immune cells is essential for: 1) understanding how neurogenesis can be affected in such a specialized niche and 2) applying the knowledge gained for the treatment of cognitive and/or motor deficits arising from inflammation-associated diseases like stroke, traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease. This review is written to provide the reader with up-to-date information explaining how these inflammatory components are effecting changes on neurogenesis.

Introduction Neuroinflammation and neurogenesis is a hot topic in contemporary neuroscience, and remains a subject of intensive investigation that has been indicated by notable studies (BenHur et al. 2003; Ekdahl et al. 2003; Monje et al. 2003). Several inflammation-associated conditions have been reported to impair neurogenesis and these include cranial irradiation, Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, traumatic brain injury (TBI), neurotoxic lesions, and even age-associated brain pathologies that include cognitive decline as a component (Monje and Palmer 2003; Ohira 2011; Richardson et al. 2007; Sparkman and Johnson 2008; Tang et al. 2009; Winner et al. 2011). In this review, we will endeavor to provide a brief yet current overview on important components of the inflammatory process that affect neurogenesis in the adult brain.

Functional roles of neurogenesis Keywords Neuroinflammation . Neurogenesis . Cytokines . Chemokines . Microglia . T cells

B. Wang : K. Jin (*) Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA e-mail: [email protected] B. Wang : K. Jin Institute of Aging and Alzheimer’s Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA

The dogma concerning the inability of the adult mammalian central nervous system (CNS) to self-repair or regenerate significantly has been held for a few decades until recently, many lines of evidence started to build the case for neurogenesis in the adult CNS (Bjorklund and Lindvall 2000; Jin et al. 2001; Nakatomi et al. 2002). In particular, neural stem/progenitor cells (NSCs) defined with the characteristics of long-term self-renewal and multi-potentiality have been shown to persist throughout life in various mammalian species including humans (Temple 2001). Neurogenesis, the process of generating new neurons from NSCs (Emsley et al. 2005; Gage 2000), mainly occurs at two discrete regions: the subgranular zone (SGZ) of the dentate gyrus (DG), and the subventricular zone (SVZ) of the lateral

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ventricle (LV) (Altman 1969; Altman and Das 1965; Duan et al. 2008). Studies have also shown that neurogenesis may occur in other areas throughout the CNS, which include the amygdala (Bernier et al. 2002), brainstem (St-John 1998), neocortex (Magavi et al. 2000), spinal cord (Chen et al. 2004; Yamamoto et al. 2001), substantia nigra (Zhao et al. 2003), and tegmentum (Hermann et al. 2006). The neurogenic process is thought to encompass a number of steps: from proliferation to migration, survival, and finally integration of the newly formed neurons into the circuitry of the CNS (Ming and Song 2005). Briefly, hippocampal NSCs proliferate and give rise to transient amplifying progenitors (TAPs), which then differentiate into immature neurons, migrate to the granule cell layer, and mature into new granule neurons. These matured neurons send projections to the CA3 and hilus regions while receiving input from the entorhinal cortex. Similarly, NSCs in the SVZ proliferate, generate TAPs, differentiate into immature neurons, and then migrate in chains along the rostral migratory stream (RMS) to the olfactory bulb (OB), where they further differentiate into interneurons. A functional role for adult hippocampal neurogenesis in spatial learning and memory has been well established (for reviews, see Deng et al. (2010) and Aimone et al. (2011)) while neurogenesis in the SVZ generates new neurons destined for the olfactory bulb to function in fine olfaction discrimination (Conover and Shook 2011). In contrast to physiological conditions, the neurogenic process having undergone events or insults such as cerebral ischemia, display a few differences under pathological circumstances. We (Jin et al. 2001) subjected rodents to focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion (MCAO) and reported a transient increase in NSC proliferation rates in the two neurogenic regions, the SVZ and SGZ. The generated neuroblasts were then shown to migrate toward the ischemic striatum, and further differentiate into mature striatal neurons. Three groups (Arvidsson et al. 2001; Jiang et al. 2001; Parent et al. 2002) further confirmed that neuroblasts from the SVZ and SGZ had the capacity to migrate into the injured brain region, differentiate into the neuronal phenotype specific to the injured area, establish appropriate long distance connections, and integrate into the neuronal circuitry. It has also been reported that various insults stimulate the proliferation of endogenous progenitors either in known neurogenic sites (Fallon et al. 2000; Gould and Tanapat 1997; Liu et al. 1998; Magavi et al. 2000) or in regions where neurogenesis normally does not occur (Johansson et al. 1999). However, the ability of proliferating NSCs to replace lost neurons is limited. Although many neuroblasts migrate to the site of injury and differentiate into new neurons, about 80 % or more of these new neurons would die shortly after generation (Arvidsson et al. 2002; Ekdahl et al. 2001). Arvidsson et al (2002) suggested two major reasons: 1) the injury site is a highly unfavorable environment

that lacks trophic support and connections necessary for neuronal survival and 2) severely damaged tissue may have certain effects on the newly generated neurons. To this day, the mystery involving the low survival rate remains unaccounted for. To determine the role of injury-induced neurogenesis in brain repair and recovery, we produced transgenic mice that express herpes simplex virus thymidine kinase (TK) under control of the promoter for doublecortin (DCX), a microtubule-associated protein expressed in newborn and migrating neurons. After treatment with the antiviral drug ganciclovir (GCV) for 14 days, DCX-expressing and BrdUlabeled cells from the SVZ and SGZ are depleted. GCV treatment of DCX-TK transgenic, but not wild type, mice also saw increased infarct sizes and exacerbated sensorimotor behavioral deficits after ischemic stroke, suggesting that injuryinduced neurogenesis contributes to stroke outcome (Jin et al. 2010). Using a transgenic mouse model containing a modified HSV-TK gene driven by the nestin promoter, Sun et al. (2013) demonstrated that mice with reduced neurogenesis compared with those with an intact NSC pool saw worsened learning and memory outcomes. In addition, they also found that the ablation of NSCs was associated with a decreased retrograde spread of the polysynaptic marker PRV in the perforant pathway, suggesting a possible role of reduced synaptic connectivity in impaired cognition. Interestingly, they found that there was no difference in motor function after ischemic stroke following the depletion of NSCs. A probable explanation is that at 12 weeks after dMCAO (distal middle cerebral artery occlusion), the natural recovery of motor function in all experimental groups rendered the difference below detection threshold.

Neuroinflammation Neuroinflammation is a complex cellular and molecular response to stress that attempts to contain the injury or infection by way of clearing pathogens, dead or damaged host cells, and aid in returning the damaged area to its normal state. Beneficial as it may sound, inflammation also presents itself as a detriment. Neuroinflammation has been implicated in many CNS diseases including both acute brain damage and chronic neurodegenerative disorders for example cerebral ischemia, multiple sclerosis, cranial irradiation, AD, PD, amyotrophic lateral sclerosis (ALS), human immunodeficiency virus dementia, and spinal cord injury (Covey et al. 2011). Many of these neurodegenerative conditions are characterized by proinflammatory cytokine changes and increased numbers of activated microglia (Voloboueva and Giffard 2011; Wang et al. 2009). Therefore, inflammation is one key pathological change observed during brain damage (Chan 1996; Lee et al.

Metab Brain Dis Table 1 Studies of anti-inflammatory strategies and their effects on neurogenesis Anti-inflammatory strategy

Effect on neurogenesis

Knockout studies

Transgenic mice studies

References

IL-6 blockade using Indomethacin Activation of TNF-R1

Increase Decrease

– −

Monje et al. (2003) Iosif et al. (2006)

Activation of TNF-R2 Blockade of endogenous TNF-α

Increase Decrease

− –

Chen and Palmer (2013)

Physical activity (Conditioned running) Repopulation of peripheral CD4 T cells in RAG2−/− mice thus increasing BDNF production Depletion of T and B cells Depletion of CD4 T cells

Increase Increase

– TNF-R1−/− TNF-R2−/− TNF-R1/R2−/− TNF-R1/R2+/+ TNF-R1−/− TNF-R2−/− TNF-α−/− – RAG2−/−

– –

Speisman et al. (2013) Wolf et al. (2009a)

Increase Increase

–

CB-17/Icr-+/+Jcl CB-17/Icr-scid/scid

Saino et al. (2010)

Depletion of CD25+ cells

Decrease

1999; Ying 2007) that may in turn be a valuable therapeutic target in the treatment of brain injuries. Inflammation in the brain, however, is different from that in peripheral tissues in a few ways such as the initiation of and the brain’s sensitivity to inflammation. The brain is immuneprivileged because of its protection by the blood-brain barrier (BBB), which only allows certain cells and molecules to enter and exit the CNS (Hickey 2001). The inflammatory response in the brain to an injury sees an increase in reactive oxygen species (ROS) resulting from the death of neurons, triggering the increase of pro-inflammatory cytokines and chemokines. These factors upregulate adhesion molecules and activate microglia, which prompt the increase in the expression of metalloproteinases and cytokines to allow for the infiltration of innate and adaptive immune cells from the periphery (Wang et al. 2007). The release of these factors can disrupt the BBB, sustain the recruitment and activation of leukocytes and microglia thus creating a positive feedback loop, which prolongs inflammation and contributes to ongoing neuronal damage (Iadecola and Anrather 2011; Leker and Shohami 2002; Ziebell and Morganti-Kossmann 2010). Dependent upon the time and severity of the inflammation, it is apparent that the inflammatory response in the acute phase is widely shown to be detrimental while inflammation at the chronic phase may be essential for repair and regeneration (Bowen et al. 2006).

The effect of cytokines on neurogenesis Cytokines are a group of proteins that act as chemical messengers between cells of the immune system. In the brain, proinflammatory cytokines are mainly produced by activated microglia as part of the innate immune response. Attempts

have been made to dissect the individual roles of some of these potent inflammatory mediators in the regulation of neurogenesis (see Table 1). Interleukin-6 (IL-6) IL-6 was first known as a B cell differentiation factor, because it possessed the capability to induce B cells to mature and produce antibodies (Hirano et al. 1985). Over the years, IL-6 grew in popularity due to its involvement in immune responses, and more recently, in neuroimmunity. Vallieres et al. (2002) indicated that when IL-6 was chronically expressed in the astroglia of young adult transgenic mice, there was a significant decrease (63 %) in the rate of new neurons being produced. The progenitor cell distribution and gliogenesis, however, remained normal. Monje et al. (2003) exposed NSCs to recombinant IL-6 and TNF-α and observed that neurogenesis was dramatically decreased. The group went on to show that IL-6 blockade alone was enough to restore neurogenesis. Coupled with results from the study by Vallieres et al. (2002), IL-6 was then implicated as the pivotal cytokine suppressing neurogenesis. Taga and Fukuda revealed that cytokines in the IL-6 and bone morphogenetic protein (BMP) families act in concert to inhibit neurogenesis and promote astrocytogenesis (Taga and Fukuda 2005). Namihira and Nakashima then went on to suggest that the Janus Kinase and Signal Transducer and Activator of Transcription (JAK/ STAT) 3 pathway initiated by members of the IL-6 family of cytokines is essential for astrocyte differentiation from NSCs (Namihira and Nakashima 2013). Furthermore, data from Li et al. (2012) showed collectively that the RAF/MEK/ERK pathway modulates the JAK/STAT3 pathway by regulating gp130 expression in NSCs and consequently contributes to the process of NSCs switching from neurogenesis to astrocytogenesis.

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Tumor necrosis factor alpha (TNF-α) TNF-α is upregulated in most if not all immune responses as well as in a myriad of neurodegenerative diseases. Ben-Hur et al. showed that TNF-α is anti-proliferative, as upon TNF-α treatment, NSCs uptake of BrdU was reduced in a dose-dependent manner, but induction of apoptosis was not seen (Ben-Hur et al. 2003). Further study (Liu et al. 2005) showed that the expression of a neuron-specific cytoskeletal protein, microtubule-associated protein (MAP)-2, was decreased when cultured NSCs treated with recombinant TNF-α for 7 days, suggesting that TNF-α has a probable inhibitory effect on neuronal survival and differentiation. Remarkably, the effect of TNF-α on hippocampal neurogenesis is dependent upon which receptor, TNFR1 or TNF-R2, is being activated. The attention here then shifts from the ligand acting alone to the ligand acting in concert with a specific receptor subtype to activate a specific pathway that has the ability to regulate neurogenesis. A study (Iosif et al. 2006) reported that TNF-R1−/− and TNF-R1/2−/− mice showed a significant elevation in NSC proliferation and generation of neurons in the dentate SGZ. Those bearing TNFR2−/−, however, showed reduced neurogenesis. This clearly indicates TNF-R1 signaling acting as a suppressor of NSC proliferation in both the intact and pathological brain, and conversely, signaling through TNF-R2 increases proliferation and survival rate of newly formed neurons. Chen and Palmer further reiterated the fact with their recent study (Chen and Palmer 2013), that TNF-R2 signaling proved to be more neuroprotective in irradiation injury compared to the pro-inflammatory TNF-R1 signaling. However, they also noted an increased fraction of cells adopting a neuronal fate with the loss of TNF-R2, thus opening a new avenue of exploring potential detrimental effects with TNF-R2 signaling. Future studies using engineered TNF-α activating TNF-R2 specifically (Fischer et al. 2011), may help to shed light on the precise TNF-R1 vs TNF-R2 signaling in NSCs under normal and pathological circumstances. Interferon gamma (IFN-γ) IFN-γ is a potent proinflammatory cytokine produced by activated microglia, but its effect on suppressing neurogenesis in vivo was not significant (Monje et al. 2003). In vitro results, however, showed otherwise. Using neurospheres, Ben-Hur et al found that IFN-γ significantly increased the rate of apoptosis and inhibited NSC proliferation (Ben-Hur et al. 2003). Wong et al. (2004) also reported that IFN-γ increased the percentage of total βIII-tubulin-positive cells by about 3 fold in a 24 h period. In addition, IFN-γ not only directly promotes the neuronal differentiation of NSCs (Kim et al. 2007), but also can activate microglia to achieve the same result (Butovsky et al. 2006). One would surmise that there would be differences between in vitro and in vivo models, and more so variations between the types of cell lines and animal models used, as well as the region of the brain being studied. Kim et al. (2007) further stated a plausible explanation owing to

their findings: in both physiological and pathological environments, neurogenesis might be stimulated across a varying range of IFN-γ concentrations. Of note, they first reported that c-Jun N-terminal protein kinase (JNK) signaling is involved in NSCs differentiation to neurons in response to IFN-γ. They also found the activation of p38 MAP kinases at the point where the concentration of IFN-γ was suppressing NSC proliferation, suggesting that IFN-γ could be causing stress to the cell, following the thought that p38 MAP kinases and JNK are robustly activated by different cellular stresses like pro-inflammatory cytokines and UV irradiation. A recent in-depth in vitro study of IFN-γ by (Walter et al. 2011), however, attempted to refute the longstanding view that IFN-γ is indeed beneficial for neurogenesis. The group first showed that IFN-γ exerted a cytotoxic influence on NSCs by significantly increasing caspase 3/7 activity and thereafter, showed that IFN-γ was antiproliferative on NSCs as the percentage of BrdU-labeled cells significantly decreased when E14 neurosphere-derived cells were treated with IFN-γ. Next, the study found that IFN-γ treatment on E14 neurospherederived cells caused the significant upregulation not only of βIII-tubulin or MAP2a-c transcripts, but also of GFAP indicated by real-time quantitative PCR data. Further immunocytochemical studies found that IFN-γ could drive NSC differentiation towards an abnormal marker profile: GFAP+/βIII-tubulin+, wherein these cells are functionally distinct from neurons and mature astrocytes, indicated by electrophysiological results. To add, the group also showed that IFN-γ treatment led to the upregulation of sonic hedgehog (SHH) signaling paralleled by a downregulation of Gli1 being the cause for promoting an abnormal dysfunctional NSC-derived phenotype (GFAP+/βIIItubulin+) that is completely unrelated to classical views of neurons and astrocytes. Taken together, the results from Walter et al. (2011) mainly showed that IFN-γ may instead reduce the population extent of NSCs and be anti-neurogenic, and these results should further be confirmed by in vivo studies. IL-1β Many groups have shown the involvement of IL-1β or the lack thereof in neurogenesis (Ling et al. 1998; Liu et al. 2005; Monje et al. 2003; Wu et al. 2012a), and its effects are mediated by at least two mechanisms: direct or indirect. Of interest is the direct effect of IL-1β interaction with IL-1β receptor, IL-1R1, expressed by NSCs in the SGZ of the DG (Arguello et al. 2009; Koo and Duman 2008) but not by those found in the SVZ (Ben-Hur et al. 2003). Koo and Duman (2008) administered IL-1β in vitro and in vivo and showed that exposure to IL-1β yielded a decreased rate of hippocampal NSC proliferation, which was attributed to the activation of the nuclear factor-kappa B (NFκB) signaling pathway. Further, chronic expression of human IL-1β using a recombinant adenoviral vector in the DG in vitro and in vivo yielded a decrease in neurogenesis (Mathieu et al. 2010). Recently, IL1β has also been implicated as having an anti-neurogenic

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property in times of acute and chronic stress (Ben MenachemZidon et al. 2008; Koo and Duman 2008). Elevation of IL-1β levels has also been reported in neurodegenerative diseases like AD due to the activation of the NALP3 inflammasome (Halle et al. 2008). This activation however, was only possible with the phagocytosis of fibrillar state of Aβ by microglial cells. Because microglial cells are incapable of degrading fibrillar Aβ even after a few weeks since its internalization, a loss of lysosomal integrity may occur, thus resulting in the release of lysosomal components into the cytoplasm. These released components were touted to initiate the Aβ-induced IL-1β pathway, as IL-1β release was dependent on cathepsin B, a lysosomal protease. Further studies pointed out that cathepsin B was found to act ‘upstream’ of NALP3 instead of regulating pro-IL-1 production or release of mature IL-1β. These results then beg the question of: 1) whether microglial phagocytosis of neuronal cells during inflammation is an efficient or even an over-efficient process; 2) and if not, does that lead to a loss of lysosomal integrity as indicated above thereby releasing lysosomal factors like cathepsin B that contribute to NALP3 activation; 3) whether inhibition of the inflammasome along with IL-1β or even cathepsin B are plausible therapeutic targets for enhancing neurogenesis. In fact, phagocytosis of neuronal cells may be an over-efficient process as shown in a recent study by Neher et al. (2013). They reported that inhibition of phagocytosis by macrophages and microglial cells could delay neuronal death after brain ischemia and improve functional outcome after stroke. This observation is based on the supported premises that: 1) the ‘eat-me’ signal phosphatidylserine (PS) can be exposed on neurons as a result of activation or the presence of sublethal stimuli; 2) two phagocytic proteins, MerTK and MFG-E8, required for phagocytosis of PS-exposing cells are transiently upregulated after focal ischemia. IL-18 This pro-inflammatory cytokine belongs to the IL-1 family of cytokines, and is being expressed at high levels following the activation of microglia (Conti et al. 1999). The study of its role in regulating neurogenesis is still unclear as shown by a recent PubMed search yielding less than 10 results using keywords “IL-18” and “neurogenesis”. As far as current literature is concerned, IL-18 has been shown to be antineurogenic in embryonic NSC culture (Liu et al. 2005), but pro-neurogenic in aging male rats in that it stimulates hippocampal neurogenesis (Speisman et al. 2013). More effort needs to be devoted to explore IL-18’s role in neurogenesis.

The effect of chemokines on neurogenesis Chemokines are a family of secreted signaling proteins that has a major role in guiding the migration of cells by attracting

cells via the increasing concentration gradient towards the source of the chemokine. NSC migration to the inflammation site is a vital step for recovery from loss of neurons due to inflammation. Therefore, the release of these chemoattractants plays a crucial role in determining the extent of repair. Several studies have reported the presence of various chemokines in the CNS, and their associated receptors widely expressed on NSCs for example, stromal cell-derived factor-1 alpha (SDF1α)/CXCR4, monocyte chemoattractant protein-1 (MCP-1)/ CCR2 (Imitola et al. 2004; Peng et al. 2004; Widera et al. 2004). SDF-1α When released from activated astrocytes, SDF-1α signals NSCs to migrate to the site of neuronal damage (Belmadani et al. 2006; Imitola et al. 2004). Through the work of Ni et al. (2004) and Peng et al. (2004), its receptors CXCR4 and CXCR7 are now known to be highly expressed on NSCs. Apart from inducing the migration of NSCs, SDF-1α promotes NSC proliferation (Imitola et al. 2004; Gong et al. 2006) and survival (Dziembowska et al. 2005; Krathwohl and Kaiser 2004; Molyneaux et al. 2003) in vitro. Wu et al. also showed that SDF-1α enhances human NSC proliferation via the Akt/FOXO3a signaling (Wu et al. 2009). They reported that NSC proliferation increased with phosphorylation of Akt1 and FOXO3a and that it is time and dose dependent. Also, by overexpressing the dominant-negative Akt1 or wildtype FOXO3a in human NSCs, the group did not observe any SDF-1α mediated proliferation. Recently, a study by (Zhu et al. 2012) found that SDF-1α enhances the survival of human NSCs via its interaction with CXCR7, which has a 10-fold higher affinity than CXCR4 (Burns et al. 2006), and may have triggered the ERK1/2 signaling pathway upon apoptotic challenges. SDF-1α was also reported to participate in enhancing GABAergic inputs to new neurons (Ardelt et al. 2013), suggesting the importance of SDF-1α in coordinating neurogenesis and neovascularization after an ischemiareperfusion injury. MCP-1 MCP-1 is another important chemokine that is upregulated during inflammation and induces NSC migration. It was shown to be inducible by TNF-α in U373 cells (Schwamborn et al. 2003). Widera et al. (2004) also showed that the receptor for MCP-1, CCR2, was widely expressed on NSCs, and that interaction with its ligand, MCP-1, activated the migration of rat-derived NSCs. Belmadani et al. (2006) further discovered that in hippocampal slice cultures injected with inflammatory stimuli, NSCs migrated toward the injection site, and that their survival was worse compared to the control group. The group also reported that CCR2−/− mice had significantly impaired NSC migratory pattern and migration, which indicate that the MCP-1 chemokine gradient is necessary for the migration of NSCs to the inflammatory site. Wu et al. (2012b) further supported the results by showing that

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SDF-1α and MCP-1 released by astrocytes attracted NSCs in the presence of IL-1β injection into the brains of severe combined immunodeficiency (SCID) mice. More interestingly, a recent study (Lee et al. 2013) reported that intracerebral transplantation of soluble MCP-1 derived from bone-marrowderived mesenchymal stem cells into Niemann-Pick type C mice could also enhance SVZ NSC proliferation and neuronal differentiation. This means that instead of transplanting cells, soluble factors like MCP-1 could be used to stimulate NSC proliferation and promote differentiation to neurons thus eliminating the need to ensure a high percentage of survival of transplanted cells, which is touted to be one of the more difficult hurdles to overcome in the field of stem cell transplantation.

The effect of immune cells on neurogenesis There is a plethora of literature that has been published with regards to the actions of immune cells in the brain on neurogenesis, but we will limit our discussion to include current findings available on the more prominent ones. Microglia, astrocytes, and neurogenesis One indication of neuroinflammation is the activation of microglia. This phenomenon is, however, not pro- or antineurogenic per se as the overall outcome relies on the balance of pro- and anti-inflammatory actions of the secreted molecules (Ekdahl et al. 2009). Two groups have successfully modeled acute microglial activation via exogenous administration of lipopolysaccharide (LPS) (Ekdahl et al. 2003; Monje et al. 2003), but we are not to assume that this model reflects all the microglial functions as its functional phenotypes—resting, classically activated, or alternatively activated—depends on the particular microenvironment that they are in (Hanisch and Kettenmann 2007; Kohman and Rhodes 2013). In a broad sense, it is widely accepted that acute microglial activation along with secreted pro-inflammatory cytokines like IL-6, TNF-α, IFN-γ, and IL1β have the ability to suppress neurogenesis in vitro (Ben-Hur et al. 2003; Cacci et al. 2005; Cacci et al. 2008; Iosif et al. 2006; Koo and Duman 2008; Monje et al. 2003). Chronic microglial activation could, however, be beneficial as opposed to detrimental in certain conditions. Morgan et al. (2004) showed that microglia could release neurotrophic factors like basic fibroblast growth factor (bFGF) and brainderived neurotrophic factor (BDNF) while Shaked et al. (2005) further supported that fact by showing that T cells or their cytokines can influence microglia to take on another phenotype that counteracts glutamate-mediated neurotoxicity by way of facilitating glutamate clearance. Recently, a study

surfaced indicating that the amount of microglia could in actuality inhibit NSC proliferation in the absence of inflammatory stimuli i.e., under physiological conditions, based on correlation analysis (Gebara et al. 2013). This study raised a few discrepancies versus other studies (Olah et al. 2009; Ziv et al. 2006) for example; differences in housing conditions, strain of animal used, and diet. Although the strain of the animal used was not a factor in the concluding results claiming support from Sultan et al. (2013), environmental factors as well as housing conditions may indeed have influenced the results. Even so, the results for the in vitro experiment i.e., coculture of NSCs with microglia, and NSCs with astrocytes in and of itself raises questionable doubt: 1) Song et al. (2002) observed that astrocytes did indeed increase the rate of proliferation of adult NSCs; 2) The background of the strain of transgenic mice used in the study, FVB/N, may have an increased basal inflammation level, and perhaps may have posed as a limitation, but a study by Wang et al. (2011) involved activating astrocytes using LPS, which is analogous to the increased basal inflammation level (although the level may vary indefinitely), reported that activated astrocytes secreted IL-6 to increase NSC proliferation and differentiation as opposed to inhibiting it; 3) The microglial phenotype for that specific microenvironment instead of the amount of microglia present in the co-culture should have taken precedence as a factor for causing the decrease in the number of NSCs. Taken together, these provide evidence that may have rendered results of Gebara et al. (2013) in vitro co-culture experiment to be inconclusive. On the other hand, the idea that interaction between NSCs and microglia under physiological conditions can result in suppressed neurogenesis is novel nonetheless, but should be pursued with thoughtful experimental design in mind. T cells, B cells and neurogenesis Under physiological conditions, T cells are barely found in the CSF (~150,000) and memory T cells make up the bulk (~80 %) of them (Engelhardt and Ransohoff 2005). CD4 T-cells CD4 T cells have the ability to promote and maintain neurogenesis by: 1) the activation of microglia via specific cytokines released by the different T cell subsets like T helper 1 (Th1) releasing IFN-γ (Butovsky et al. 2006) and 2) regulating insulin growth factor 1 (IGF-1) import into the brain, which consequently regulates neuronal BDNF production found in the DG of the hippocampus (Ziv et al. 2006; Ziv and Schwartz 2008). Interestingly, this promotion and maintenance of neurogenesis occur through peripheral CD4 T cells (Schwartz and Shechter 2010; Wolf et al. 2009b). To elaborate, Wolf et al. (2009a) showed that systemic depletion of CD4 T cells saw a significant decrease in DG neurogenesis accompanied by decreased BDNF expression in the brain, and impaired reversal learning in the Morris water maze.

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However, depletion of B cells or CD8 T cells had no such effect. Repopulation of RAG2−/− mice with only CD4 T cells increased: 1) NSC proliferation, indicating that systemic activity of CD4 T cells is essential in maintaining DG neurogenesis; 2) BDNF levels thus implying that CD4 T cells have a hand in regulating BDNF levels (see Table 1). Therefore, how peripheral CD4 T cells modulate neurogenesis in the DG remains unclear, but Huang et al. (2010) offers an in-depth explanation using genetic and functional analyses. Under pathological conditions like multiple sclerosis (MS), which is a widely studied neuroinflammatory disease that uses experimental autoimmune encephalomyelitis (EAE) as its model, Kooij et al. (2010) showed that activated CD4 T cells had a hand in impairing brain endothelial P-glycoprotein (Pgp) function thus allowing perivascular infiltrates containing lymphocytes to cross the BBB. As an aside, crossing the BBB under inflammatory conditions however, does not seem to be the only way activated immune cells can enter the brain. Using EAE, Engelhardt et al. (2001) showed that the choroid plexus expressed MAdCAM-1, ICAM-1, and VCAM-1, and its ultrastructure was poised to bind immune cells via their known ligands. Kleine and Benes (2006) echoed that finding by suggesting that immune cells can survey the CNS of a healthy individual by way of transmigrating from blood vessels into the choroid plexus stroma to move within the CSF. CD8 T cells More often than not, infiltrates consisting predominantly of activated CD8 T cells are found in the SVZ where NSCs are localized (Matsushita et al. 2008; Friese et al. 2008). These activated CD8 T cells then release granzyme B (GrB), which has been shown to inhibit neurogenesis via activation of the Giα/Go-coupled receptor (Wang et al. 2010). Stimulation of the Giα/Go-coupled receptor then led to a decrease in cyclic AMP (cAMP) levels, which increased the expression of Kv1.3 channels on NSCs. Wang’s group further suggested the importance of pharmacologically blocking Kv1.3 channels on NSCs as doing so resulted in increased NSC differentiation into neurons. Th1 and Th2 cells In general, Th1 cells are mostly known for being detrimental via the release and the action of its main cytokine IFN-γ. Th2 cells, on the other hand, are known to be neuroprotective via the release and action of its main antiinflammatory cytokine IL-4 (Xiong et al. 2011). A study (Butovsky et al. 2006) showed differential effects of IL-4activated in the presence of IGF-1 and IFN-γ-activated microglia in that they promote oligodendrogensis and neurogenesis respectively in vitro. In another study (Xiong et al. 2011), used an IL-4 knockout (KO) mouse model to illustrate the effects of the absence of IL-4 signaling after transient MCAO. They found that the outcome after the induction of stroke was worse and reported increased inflammation in the core. Surprisingly, the effects were reversed with

exogenous IL-4 administration in the IL-4 KO, but not in wild type mice. A plausible reason was that they observed an increased Th1/Th2 ratio in IL-4 KO but not in wild type mice, which may play an essential role in decreasing inflammation in the core. More importantly, the effects of Th1 and Th2 cells in the context of neuroinflammation affecting neurogenesis has not been widely studied, thus future studies may be directed to answer these concerns. Tregulatory cells (Tregs) Tregs have been implicated in maintaining both immunological self-tolerance and homeostasis (Vadasz et al. 2013). There are several subsets of Tregs but FoxP3+CD25+CD4+ Tregs specifically, have garnered quite an attention because of their involvement in immune reactivity suppression including inflammation-associated CNS conditions like AD, PD, TBI, and stroke (Walsh and Kipnis 2011). The involvement of FoxP3+CD25+CD4+ Tregs in the regulation of neurogenesis is still unclear. Ishibashi and colleagues subjected spontaneously hypertensive rats (SHRs) to permanent MCAO and primed E-selectin Tregs by way of repetitive intranasal recombinant E-selectin administration. Eselectin-tolerization showed suppressed TNF-α levels and increased neurogenesis thereby suggesting that these Tregs had the ability to modulate neurogenesis and promote brain repair after stroke (Wolf et al. 1996). In another report, using a highly reproducible model of cortical infarction in mice, the effect of each subset of T cells on neurogenesis was studied by depleting each subset of T cell at a time (see Table 1). Removal of T cells, especially the CD4+ population, saw an increase in NSC proliferation, followed by an escalated improvement in functional recovery. On the other hand, removal of CD25+ population, of which includes the Tregs, saw a decreased rate of neurogenesis and impaired functional recovery (Saino et al. 2010). This study implicates the role of T cells in the regulation of post-stroke neurogenesis and requires further study to pinpoint which subsets of T cells are indeed beneficial or detrimental to the promotion of neurogenesis. B cells B cells have been implicated in disease conditions such as MS, in that short-lived plasmablasts were identified as the main effector B cell population present in significant numbers that perpetuated the ongoing active inflammation in MS patients (Cepok et al. 2005). Wolf et al. (1996) identified a subset of B cells known as B-regulatory cells (B-regs), which is now known to be present in humans and is able to depress Th1 proliferation (Fillatreau et al. 2002; Vadasz et al. 2013). The stimulatory conditions for B-regs are still to be determined and are important to understand how it suppresses or regulates other immune cells. If B-regs are indeed implicated in immunity, this may open up a new avenue to determine its effects on neurogenesis.

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Conclusion Over the past decade, we have witnessed the emergence of key cytokines, chemokines, and inflammatory cells that are critical to our knowledge base of neuroinflammation. To this end, studies on neuroinflammation and its effects on neurogenesis have increased our understanding progressively to see the complexities involved. Though it can be easy to slip into a mindset of compartmentalization—where different inflammatory components do not act as an entity rather, as individual factors—we need to keep in mind that these factors may very well have very different outcomes on neurogenesis when acting synergistically. An increase in the Th1/Th2 ratio can decrease inflammation in the core after ischemic stroke (Xiong et al. 2011), while IL-6 acting in concert with BMP inhibits neurogenesis and promote astrocytogenesis (Taga and Fukuda 2005) pose a major challenge to the neuroinflammation and neurogenesis field: To devote efforts to intensify studies to elucidate the mechanistic details involving the combined actions of different cytokines, chemokines, and even inflammatory cells to gain a more accurate picture of what is occurring physiologically and under pathological circumstances. Furthermore, since slight alterations of the microenvironment may allow neurogenesis to occur (Nakatomi et al. 2002), it is also important to recognize the physiological or pathological microenvironment where NSCs find themselves in, thus bringing to light the challenges involved in finding appropriate combinations of pharmacotherapeutic agents to provide the best possible microenvironment to enhance neurogenesis during the course of inflammation. Acknowledgments This work was partially supported by National Institute of Health (NIH) grants AG21980 and NS057186 (KJ).

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