Neuroimmune Pharmacology from a Neuroscience Perspective

INVITED REVIEW

Neuroimmune Pharmacology from a Neuroscience Perspective

Nicole A. Northrup & Bryan K. Yamamoto

Received: 19 April 2010 /Accepted: 2 August 2010 /Published online: 18 August 2010# Springer Science+Business Media, LLC 2010

Abstract The focus of this commentary is to describe howneuroscience, immunology, and pharmacology intersect andhow interdisciplinary research involving these areas hasexpanded knowledge in the area of neuroscience, inparticular. Examples are presented to illustrate that thebrain can react to the peripheral immune system andpossesses immune function and that resident immunemolecules play a role in normal brain physiology. Inaddition, evidence is presented that the brain immunesystem plays an important role in mediating neurodegener-ative diseases, the aging process, and neurodevelopmentand synaptic plasticity. The identification of these mecha-nisms has been facilitated by pharmacological studies andhas opened new possibilities for pharmacotherapeuticapproaches to the treatment of brain disorders. The emergingfield of neuroimmune pharmacology exemplifies this inter-disciplinary approach and has facilitated the study of basiccellular and molecular events and disease states and opensavenues for novel therapies.

Keywords Neurodegeneration . Neuroplasticity .

Inflammation . Neurogenesis

Introduction

A burgeoning research field in the area of neuroscience isneuroimmunology and the pharmacology of immunefunction within the brain. Historically, research in neuro-science and immunology progressed independently formany years, due primarily to four reasons described byChang et al. (2009). First, the knowledge and presence ofthe blood−brain barrier (BBB) was thought to exclude mostimmune components. Second, the expression of the majorhistocompatibility complex (MHC), which presents antigento T-lymphocytes, is suppressed in the brain except in thepresence of an immune stimulus. Third, very few lympho-cytes are present in the brain, and those that infiltrate thebrain undergo apoptosis. Fourth, the production of pro-inflammatory cytokines is limited in the brain. It is nowknown that the two systems are integrated in that the brainhas immune function and interacts with the peripheralimmune system. The following review will summarize andcomment on the current literature related to the intersectionof neuroscience, immunology, and pharmacology. Theintegration of these fields of research will be reviewedwithin the context of normal brain function, disease states,and possible pharmacotherapeutic intervention strategies(Table 1).

The brain and immune function

The brain has resident cells capable of producing moleculesthat participate in the immune response against pathogensor in response to injury. This overall response is character-ized by inflammation, mediated by both glial cells andneurons, and mimics the innate immune response in theperiphery.

Sources of Support DA07606, DA16866, and DA19486

N. A. NorthrupDepartment of Pharmacology and Experimental Therapeutics,Boston University School of Medicine,Boston, MA 02118, USA

B. K. Yamamoto (*)Department of Neurosciences,University of Toledo College of Medicine,3000 Arlington Avenue,Toledo, OH 43614, USAe-mail: [email protected]

J Neuroimmune Pharmacol (2011) 6:10–19DOI 10.1007/s11481-010-9239-2

Microglial cells are the resident brain macrophages andare the initial responders to an immunological challenge inthe brain. Upon activation, microglia will produce immunemolecules in response to a foreign pathogen or neuronalinsult and facilitate the recruitment of other immune cells.These molecules include cytokines, chemokines, comple-ment proteins, and upregulated cell surface receptors, suchas cytokine receptors and toll-like receptors (TLR) (Changet al. 2009; Lucin and Wyss-Coray 2009). TLRs in thebrain are the initial responders to an infectious agent,similar to their function in the periphery, and are known fortheir innate ability to recognize pathogen-associated mo-lecular patterns (PAMPs) expressed by microorganisms. Inaddition, endogenous ligands for the TLRs have beendiscovered and are thought to play a role in some neurode-generative processes (Walter et al. 2007; see below).Signaling through the TLRs is very similar to the IL-1receptor family, leading to the downstream activation of thetranscription factors NFκB and AP1. Similarly, signalingthrough the tumor necrosis factor (TNF) receptor family canactivate NFκB and AP1. In contrast, the gp130 receptorfamily signals through the MAPK pathways to activate AP1,but not NFκB. Both NFκB and AP1 can be activated by freeradicals and cellular stress and promote transcription of avariety of genes involved in the immune and stress response,as well as genes that modulate cell survival (Li and Stark,2002). A more recent discovery is that neurons alsoparticipate in the immune response by producing andresponding to these immune molecules.

Neurons exhibit a marked sensitivity to inflammatorystimuli such that cytokines upregulate inducible nitric oxidesynthase (iNOS) and phagocytic NADPH oxidase (PHOX)in the brain. If unchecked, these stimuli could lead to neuronaldeath via oxidative damage (Brown 2007). Therefore, the

inflammatory immune response in the brain under normalconditions must be highly regulated to minimize neuronaldamage. The stringent regulatory mechanisms for theinflammatory response in the brain are the reasons forthe historical and erroneous viewpoint that the brain andimmune system do not interact. As stated above, theseinclude (1) the presence of the BBB and other endogenousfactors, which results in the exclusion of the majority ofthe peripheral immune systems components (Hickey et al.1991); (2) the suppression of antigen presentation andsuppression of MHC expression (Neumann et al. 1998); (3)the rapid apoptosis of the minimal lymphocytes (B cellsand T cells), which gain access to the brain (Bauer et al.1995); and finally, (4) the limited ability for the productionof proinflammatory cytokines, such as TNFα and IL-1β(Perry et al. 1993). A variety of neurotransmitters andneurohormones are responsible for some of these immunosup-pressive events (Lucin and Wyss-Coray 2009; Chang et al.2009). For example, norepinephrine (NE), vasoactive intes-tinal peptide (VIP), and glutamate are capable of suppressingMHC class II expression in astrocytes (Frohman et al. 1988;Lee et al. 1992) and NE, dynorphin, and 17β-estradiol are allcapable of suppressing microglial activation and the releaseof microglial inflammatory cytokines (Dello Russo et al.2004; Kong et al. 1997; Bruce-Keller et al. 1999).

During basal conditions in the brain, there is minimalimmune activation and a limited presence of immunemolecules. However, low levels of immune molecules arerequired in the brain for protection against foreign agents, arenecessary for normal brain development, and modulatesynaptic plasticity in the mature brain. This duality of roles inmediating normal brain function and neuronal damage, wheretoo much of a good thing can be bad, renders it necessary thatthe immune response in the brain be tightly regulated.

Table 1 Summary table indicating immune factors altered in response to various disease states and insults in the brain

MS Parkinson's Huntington Alzheimer's TBI Drug abuse HIV Aging Neurogenesis

IL-1 X X X X X X

TNFα X X X X X X X X

IL-6 X X X X X X

TGFβ X X

MCP-1/CCL2 X X X

IL-10 X X X X

IL-4 X X

NCAM X

IFN X

Prostaglandins X X X X

MMP X X X X

The immune factors and their involvement in the disease states are limited to those referenced in the text

J Neuroimmune Pharmacol (2011) 6:10–19 11

Immune molecules in normal brain physiology

Despite the paucity of immune activation and sparsepresence of immune molecules in the adult brain underbasal conditions, there is increasing evidence for the role ofimmune molecules in brain development and synapticplasticity (Boulanger 2009). More specifically, cytokinesand chemokines are involved in neuronal differentiationand migration, as well as the regulation of cell survivalduring development. For example, transforming growthfactor beta (TGFβ) is required for differentiation of progenitorcells into tyrosine hydroxylase (TH) positive dopaminergicneurons in the ventral midbrain (Roussa et al. 2006). Thechemokine CXCL12 (SDF-1) and its receptor CXCR4 areimportant for the migration of GABAergic interneurons fromthe ganglionic eminences into the cortex during embryogen-esis (Stumm et al. 2003). Furthermore, the gp130 familycytokines, specifically cardiotrophin-1 (CT-1) and leukemiainhibitory factor (LIF), regulate motor neurons duringdevelopment and function to maintain motor axons later inlife, respectively (Holtmann et al. 2005). These are only afew of several cytokines and various immune proteins thatare involved in synaptic plasticity in the developing andmature brain. Therefore, as our knowledge of immunefactors expands, a growing list of mediators that interact tocontrol plasticity and development, which extends beyondgrowth factors alone, must be considered.

The brain undergoes two main types of plasticity:activity-dependent and homeostatic plasticity. The sameimmune proteins seem to play a similar role in both types ofplasticity in both the developing and mature brains.Neurons produce molecules of the innate immune system,such as class I major histocompatibility complex (MHCI)molecules and the complement cascade protein, C1q,during development, which play roles in elimination ofsynapses in the connections between the retinal ganglionand the dorsal lateral geniculate nucleus (Huh et al. 2000;Stevens et al. 2007). In the adult brain, MHCI alsofacilitates activity-dependent synaptic plasticity in the adulthippocampus (Huh et al. 2000). Pentraxins are proteinsinvolved in the humoral immune response. They areproduced by neurons in the brain, function to regulate thenumber of excitatory synapses in the mature brain, andare required for normal developmental synapse remodel-ing (Xu et al. 2003). These examples highlight the closesimilarities between the roles of these immune moleculesin central nervous system (CNS) development, where theyfunction to remove unwanted synapses, and in the periph-eral immune response, where they destroy and removeunwanted cells. In addition, these mechanisms for synapseelimination could have important implications for the lossof synapses in neurodegenerative diseases, where these

same molecules of the innate immune response areupregulated in neurons.

Glial cells also play a role in development and synapticplasticity. Tumor necrosis factor alpha (TNFα) released byglia is involved in synaptic scaling. TNFα has been shownto regulate excitatory and inhibitory synaptic transmissionthrough the regulation of expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) andgamma-aminobutyric acid (GABA) receptor subtype A(Stellwagen et al. 2005). Furthermore, the inflammatorysignaling molecule DAP-12, produced only by microglia,has also been found to play a role in synaptic plasticity andin modulating glutamatergic neurotransmission (Roumieret al. 2004).

Further investigation is warranted to improve ourunderstanding of these immune proteins and their roles inthe brain. Regardless, knowledge of the brain immunesystem has markedly improved our understanding ofnormal brain function and development, as well as theresponse of the brain to insults, injury, and its ability toattempt repair. The following text will attempt to illustratehow information in the field of immunology has expandedour knowledge of neurodegenerative diseases and hasprovided new opportunities for the development of phar-macotherapeutic agents for the treatment of neurodegener-ative diseases.

Neuroinflammation in neurodegenerative diseases

As discussed above, the nervous and immune systemsare closely intertwined. An additional example of thisinteraction is the prominent role the immune system playsin neurodegenerative diseases. The responses of thenervous system to infection and injury are essentially underthe control of the peripheral and brain immune systems.Although it is not clear if peripheral immune factors caninfluence neurodegenerative disease, emerging evidencesuggests that altering peripheral inflammation duringneurodegenerative disease can alter disease course. Inaddition, the brain can also react with its own immuneresponse through its activation by the predominant immunecells of the brain, microglia. Microglia are sentinels of themilieu of the brain and produce factors that affect otherglial cells, such as astrocytes, as well as neurons. Theinvasion of a pathogen or the initial appearance of tissuedamage prompts the immune system to engage in repair(e.g., phagocytosis) and then subside once the reparative orprotective process has been completed. However, undercertain conditions when the damaging stimulus persists, thesustained inflammation may result in the production ofneurotoxic mediators and eventual neuronal damage, such

12 J Neuroimmune Pharmacol (2011) 6:10–19

as that which is evident in neurological diseases and inresponse to various insults, such as mechanical injury anddrugs of abuse.

Multiple sclerosis Multiple sclerosis (MS) is a well knownneurodegenerative disease characterized by an autoimmuneresponse resulting in inflammation, demyelination, andaxon degeneration. Lesions evident in MS are marked byan increase in microglia and astrocytes, as well as theinfiltration of the brain and spinal cord matter bylymphocytes and antigen presenting cells from the plasma(Lassmann et al. 2001). In particular, there is a depositionof antibodies and complement proteins around the lesionsof demyelination resulting from the activation of both theinnate and acquired immune systems. T-cells recognizemyelin basic protein which is autoantigenic and stimulatesthe production of cytokines to activate NFκB and AP1. Inthe presence of IL-6 and TGFβ, T cells will express retinoicacid receptor-related orphan receptor γt and differentiateinto Th17 cells that secrete IL-17 and TNFα to producedamage to myelin (Glass et al. 2010). The furtherprogression of MS is mediated by T and B lymphocytes,which amplify the autoimmune responses.

Alzheimer's disease Examples of inflammatory responsesin the brains of Alzheimer's patients include astrogliosisaround senile plaques and proinflammatory mediatorsincluding MHCI, COX-2, MCP-1, TNFα, IL-1β, and IL-6(Akiyama et al. 2000). Elevated levels of chemokines,cytokines, and their receptors have also been described inconjunction with the activation of microglia that may beprecipitated by Aβ aggregation, the classic biomarker of thedisease. The resultant increase in these inflammatorymediators can promote neuronal death evident in Alzheimer'sdisease (AD) (Akiyama et al. 2000). The detection of Aβ bymicroglia and astrocytes may occur through the activation ofTLR 2 and 4 to stimulate transcription factors (NFκB andAP1) and activate inflammatory response genes (Walter et al.2007). Other receptors that have been shown to mediate theinflammatory response to Aβ are the receptor for advancedglycoxidation end-products (RAGE) and NOD-like receptors(NLR), both of which are expressed by microglia, cause anincrease in pro-inflammatory factors, and stimulate apoptosis(Yan et al. 1996; Halle et al. 2008). Although the roles of Aβand Aβ aggregation in the initiation of inflammation remainunclear, it is evident that proinflammatory mediators canamplify the immune response and cause a feed-forward cycleamong microglia, between microglia and astrocytes, andbetween microglia and neurons. For example, cytokinesfrom microglia can activate secretase activity in neurons(Sastre et al. 2008) and cause cell death, while TNFα andIL-1β released by microglia can activate astrocytes andcytokine release by astrocytes can activate microglia.

Parkinson's Disease Although the loss of dopaminergicneurons is the hallmark pathological feature of PD, microglialactivation and infiltration by astroglia and lymphocytes arealso prominent in the substantia nigra of PD patients (McGeeret al. 1988). In parallel with Aβ aggregation in AD,aggregation of α-synuclein has been shown to damagedopamine cells. It is this aggregation of α-synuclein that canactivate microglia and stimulate the release of TNFα and IL-1β, as well as reactive oxygen species, and nitric oxide tomodulate and cause cell death (Hirsch and Hunot 2009). Aninteresting observation is that the increased expression ofgenes encoding these proinflammatory cytokines reside inglial cells within in the lateral region of the substantia nigra,and it is the lateral region that degenerates before othersubregions of the substantia nigra (Chung et al 2005). Thesefindings lend credence to the hypothesis that dysregulation ofglia through immune responsivity is a pathogenic mechanismunderlying PD. Moreover, using positron emission tomogra-phy (PET), PD patients exhibit markedly elevated inflamma-tion in several brain regions, including the basal ganglia, andthat the degree of elevation is irrespective of the number ofyears with the disease (Gerhard et al. 2006). Therefore, theseresults indicate that neuroinflammation can occur coincidentwith the ongoing loss of dopamine neurons and perhaps canappear early in the disease process. In fact, the strongestevidence that neuroimmune inflammation plays a role in thepathogenesis of the disease is that dopamine neurons areexquisitely sensitive to cytokines (McGuire et al. 2001). Thismay be due to the fact that dopamine neurons contain ironand are subject to oxidative processes and hydroxyl radicalproduction resulting from the Fenton reaction. This predis-position of dopamine neurons may therefore render themvulnerable to inflammatory stimuli, infections, and environ-mental toxins that can stimulate the neuroimmune responseand microglial activation to initiate a feed-forward process.Regardless of whether inflammation is the initial cause ofdisease, the self-perpetuating process of cytokine release,microglia activation, neuronal death, and further activationand clustering of microglia around the increase in cellulardebris promotes the progressive degeneration of dopamineneurons that is characteristic of PD.

Traumatic brain injury and infections The neuroinflamma-tory responses to traumatic brain injury (TBI) and infec-tions are triggered by several factors described abovethat are released from astrocytes and microglia. Theseinclude cytokines, interlukin-1 and TNFα, chemokines, andadhesion molecules. A major driving force in the inflam-matory response to TBI is the activation of cytokine genes(Tchelingerian et al. 1994) that promote the release ofTNFα, IL-1, and IL-6, leading to the aggravation of braininjury. Supporting evidence for their role in the exacerba-tion of TBI and secondary brain injury is provided by


evidence showing that specific cytokines can exacerbatebrain damage and that specific cytokine antagonists canreduce ischemic brain damage and improve neurologicaloutcome (Lucas et al. 2006; Ghirnikar et al. 1998; Rothwelland Luheshi 2000). TNFα is present in the CSF and serumof TBI patients, which, in turn, has been shown to increasethe synthesis of several other cytokines, upregulate theexpression of chemokines, promote astrogliosis, and in-crease metalloproteinase activity that can break down thecellular matrix and increase the permeability of the BBB(Shohami et al. 1999).

Similar to TNFα, IL-1β is involved in TBI and actssynergistically with TNFα to contribute to brain injury andinfection. IL-1β can stimulate TNFα and IL-6 productionby astrocytes, whereas antibodies to IL-1α and β (Lu et al.2005) or the administration of IL-1R antagonist (Tehranianet al. 2002) can attenuate the neurotoxic effects of TBI.In addition, blockade of pro-IL-1β converting enzymereduced brain damage to ischemia. Along similar lines,bacterial infection with endotoxins such as lipopolysaccarideupregulates mRNA of IL-1R1 subtype and triggers microgliato synthesize neuroinflammatory mediators (PournajafiNazarloo et al. 2003; Cai et al. 2003).

Although a wealth of evidence supports the damagingeffects of immunoinflammatory reactions, the role ofinflammation and its cellular mediators can also play a rolein the reparative process. Reactive astrocytes can produceneurotrophic factors such as nerve growth factor (NGF) andbrain-derived neurotrophic growth factor (BDNF) andpluripotent proteins such as fibroblast growth factor(FGF), S100β and ciliary neurotrophic factor (CNTF),which can stimulate axonal growth and promote regenera-tion (Myer et al. 2006). TGF-β, IL-10, and IL-4 are examplesof endogenous anti-inflammatory mediators that can inhibitthe production of proinflammatory cytokines and MHC classII antigens (Kadhim et al. 2008; Cederberg and Siesjö 2010).These endogenous anti-inflammatory mediators are thoughtto limit the degree of damage in response to TBI or infection,restrict the extent of secondary neural damage, and increasethe rate of subsequent repair and recovery (Kadhim et al.2008). The activation of these anti-inflammatory mediators iscontrolled possibly by the differential activation of signalingpathways and the receptor interactions within local micro-environment of the damaged tissue.

Drugs of abuse and neurotoxins Illicit drugs such aspsychostimulants, cannabis, and opiates have various sitesof action and a wide range of effects in the brain; however,their common action is the alteration of immune function.Each drug alters immune function in its own unique way.More specifically, amphetamines and cannabinoids bothsuppress the peripheral immune response (Cabral 2006) buthave opposing effects on neuroinflammation.

Neurotoxic amphetamines, including D-amphetamine,methamphetamine (Meth) and 3,4-methylenedioxymetham-phetamine (MDMA, ecstasy), produce neuroinflammationthrough microglial activation and increases in the pro-inflammatory cytokines, IL-β, and TNFα (Thomas et al.2004; Orio et al. 2004; Gonçalves et al. 2008). It remainsunclear, however, whether neuroinflammation is a cause forthe neuronal damage observed with these drugs or aconsequence of the damage in order to repair the brainafter exposure to the drugs.

Minocycline, a tetracycline antibiotic and effective anti-inflammatory, reduces MDMA-induced microglial activa-tion and protects against damage to serotonergic anddopaminergic neurons in the mouse brain (Zhang et al. 2006).In addition, hippocampal neuronal damage in response to asingle neurotoxic dose of Meth is prevented by pretreatmentwith indomethacin, a non-steroidal anti-inflammatory drug(NSAID), via a decrease in glial activation and decreasedTNFα and TNF receptor 1 expression (Gonçalves et al.2010). These data suggest that neuroinflammation mediatesamphetamine-induced neuronal damage. In contrast, there aredata suggesting that the pro-inflammatory cytokine, TNFα,plays a neuroprotective role in the case of Meth toxicity suchthat pretreatment with exogenous TNFα prevented Meth-induced DA depletions typically observed in the frontal cortexand striatum. Furthermore, TNFα knock-out mice exhibit anenhanced DA depletion compared to wild-type mice inresponse to Meth (Nakajima et al. 2004).

In contrast to the inflammation produced in the CNS,psychostimulants suppress the peripheral immune systemand increase the susceptibility to infection (Cabral 2006)and comorbidity of drug abuse and human immunodefi-ciency virus (HIV) infection. HIV is a retrovirus that infectsimmune cells and ultimately leads to destruction of the hostimmune system. In late stages of HIV infection, patientssuffer from dementia. Although it is unclear exactly whatmechanisms are involved in the neuronal damage, it isevident that immune molecules play a role. In the latestages of HIV infection, elevated levels of a variety ofcytokines, including TNFα and IL-1β, and chemokines,specifically monocyte chemoattractant protein-1 (MCP-1/CCL2), are detected in serum of HIV patients. Combinedexposure to Meth and HIV infection results in the potentiationof neuroinflammatory response and enhanced damage inthe brain (Maragos et al. 2002; Flora et al. 2003; Reineret al. 2009).

Matrix metalloproteinase (MMP) expression and activityis upregulated in response to the proinflammatory cytokineproduction, and the activities of these proteases havebeen associated with increased BBB permeability. An invitro study illustrated that an incubation of HIV-infectedmonocytes/macrophages with endogenous inhibitors ofMMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1)


and TIMP-2, attenuated the increased permeability ofendothelial cell monolayers to radioactive labeled albumin.(Dhawan et al. 1995) Furthermore, human neuronalcultures exposed to Meth in combination with the HIVprotein Tat produced an enhanced release of MMP-1 andthe MMP activator, urokinase plasminogen activator (uPA)(Conant et al. 2004), suggesting that the combinedexposure to Meth and HIV enhances neuroinflammationand the eventual breakdown of the BBB. The chemokine,MCP-1/CCL2, is also partially responsible for disruptingthe BBB and facilitating the migration of HIV infected cellsinto the brain (Eugenin et al. 2006). Upon entry into thebrain, the infected monocytes and macrophages releaseviral proteins, such as Tat, gp120, and gp41, activate theresident glial cells, and promote the production of inflam-matory molecules in the brain; however, it remains unclearwhether the viral proteins themselves or the over-activation ofthe immune response in the brain is responsible for damage.

In contrast to other drugs of abuse, cannabinoidsare anti-inflammatory and capable of attenuating neuraldamage (Iuvone et al. 2009). Cannabinoids produce theiractions primarily through the cannabinoid receptors, CB1and CB2, though there has been some evidence of non-CB1and non-CB2 actions, such as those through the peroxisomeproliferator-activated receptors (PPARs) (Burstein 2005;O’Sullivan 2007; Sun et al. 2007). The CB1 receptor isprominent in the CNS on neurons, where its role is to alterneurotransmitter release, as well as on glia (Herkenham et al.1990). A synthetic CB1 receptor agonist decreased hippo-campal neuronal loss after transient global ischemia andreduced infarct volume after permanent focal ischemia in rats(Nagayama et al. 1999). Furthermore, CB1 receptor expres-sion is significantly decreased in the brains of Alzheimer'spatients and a synthetic cannabinoid, WIN55,212-2, attenu-ated beta-amyloid-induced microglial activation, cognitiveimpairment, and loss of neuronal markers in rats (Ramírezet al. 2005). The CB2 receptor is primarily localized to cellsof the immune system but has been identified in both gliaand neurons (Gong et al. 2006). The major role of the CB2receptor is the modulation of cytokine release. Activation ofthe CB2 receptor in microglial cultures, suppresses IFNγ-induced microglial activation and production of cytokinesand nitric oxide (Ehrhart et al. 2005). A third site of actionfor cannabinoids in the brain is the PPAR, nuclear receptorsthat have anti-inflammatory properties upon activation(Daynes and Jones 2002). N-oleoylethanolamine (OEA), anendogenous cannabinoid-like compound, provided neuro-protection against middle cerebral artery occlusion in wild-type but not PPARα-deficient mice, via an increase inIκB and decrease in COX-2 (Sun et al. 2007). Althoughcannabinoids are anti-inflammatory, the challenge is theidentification of a cannabinoid compound that is anti-

inflammatory but lacks psychotropic effects. Further under-standing of the cannabinoid system may provide newtherapeutic targets for the treatment of neurodegenerativediseases.

In addition to HIV, other toxins are known to causeinflammation and neurodegeneration. As noted above,inflammation plays a prominent role in the pathogenesisof Parkinson's disease. The late onset and slowly progres-sive nature of the disease has implicated early life exposureto environmental toxins such as agrochemicals and pesti-cides as risk factors for the disease (for review, see Liu et al.2003). Some of these toxins are known to activate brainimmune cells such as microglia and astrocytes to initiate aself perpetuating cycle of neuroinflammation, brain injury,further inflammation, and progressive neurodegeneration.

Neuroinflammation in aging

As several neurodegenerative diseases such as PD and ADare age-related disorders, it serves to reason that the normalprocess of aging may be superimposed on the diseaseprocess to exacerbate neuroinflammatory mechanisms andpromote cell loss. In fact, there is a substantial amount ofevidence that neuroinflammation is associated with agingand sensitizes the brain to the effects of infection or stress.

The aged brain exhibits increased numbers of activatedmicroglia, complement proteins, and primed microglia(Lucin and Wyss-Coray 2009) that permit a greater cytokinerelease upon activation (Streit et al. 2008). Moreover, thereare increased levels of IL-6 in the plasma of the elderly, andthese levels are associated with an increased risk of cognitiveimpairment (Weaver et al. 2002). Conversely, reductions inthe levels of anti-inflammatory cytokines, such as IL-10,have been observed in the aged brain, which may render theaged individual more susceptible to peripheral immuneactivation of the brain. In fact, a reduction in IL-10 isassociated with an increased vulnerability to neurodegener-ative diseases, including Alzheimer's (De Luigi et al. 2001).Consistent with this finding is a study showing that neuro-inflammation produced by peripheral immune activationexacerbates cognitive dysfunction in aged animals (Chenet al. 2008). Furthermore, aged animals appear to be moresusceptible to the deleterious effects of stress through thesensitization of neuroinflammatory mechanisms.

Stressors are well known to induce proinflammatorycytokines in the brain and can sensitize the immune responseto an immunological stimulus and exacerbate neuroinflam-mation. In fact, mild repeated stressors exacerbate neuro-inflammation in aged mice and produce more deficits inlearning and memory compared to younger adult mice(Lupien et al. 2007). Thus, aging is associated with increased


neuroinflammation that may sensitize the aged brain toinfection or stress and compromise the ability of the agedindividual to cope and recover from disease and stress.

Neuroimmune effects on neurogenesis

Neuroimmune inflammation can alter neurogenesis in avariety of ways. In general, inflammation is known tostimulate neurogenesis. Thus, neuroinflammatory responsesin several CNS diseases, such as AD, PD, ischemia, seizures,and ALS, all produce evidence of enhanced neurogenesis.Inflammatory factors such as TNFα, IL-1β, and numerouschemokines such as stromal cell-derived factor-1α (SDF-1α)and MCP-1 induce the proliferation and/or migration ofneural progenitor cells (Whitney et al. 2009), most likelythrough chemokine receptors expressed in neural progenitorcells (Ji et al. 2004).

Not only does inflammation stimulate neurogenesis, itcan also suppress neurogenesis. This duality of effect isdependent on the means by which microglia, macrophages,and/or astrocytes are activated and whether the inflamma-tion is acute or chronic. For example, microglia activatedby proinflammatory cytokines inhibit neurogenesis, butmicroglia activated by IL-4 or a low level exposure to IFN-γ associated with helper T cells induce neurogenesis(Butovsky et al. 2006). In addition, acute inflammationcan promote neurogenesis to replace the damaged neuron;however, continued recruitment of microglia and peripheralmacrophages by chemokines to the site of inflammation canresult in a chronic inflammatory response and produce afeed-forward process leading to reduced survival of newlyborn cells and neuronal damage (Whitney et al. 2009).

Pharmacology of neuroimmune responses

Understanding of the pharmacology of immune responses inthe brain has lagged behind the contribution of pharmacologyto the understanding of neurological and peripheral immuno-logical processes. This is due primarily to the traditionalmindset that the brain is an immune privileged organ. Asnoted above, this historical viewpoint is no longer true and isevidenced by the considerable crosstalk between the immuneand nervous systems and a wealth of emergent information,indicating that the peripheral immune system has the ability tomodulate multiple brain functions. Therefore, targeting theperipheral immune system for the treatment of neuroimmunedisorders in the brain cannot be discounted as a viablepharmacotherapeutic approach. It will be important todetermine which types of chronic peripheral inflammatorydiseases (i.e., arthritis, inflammatory bowel disease, infec-

tions, etc.) exacerbate certain neurodegenerative diseases.Thus, treatments for these peripheral disorders may have theadded benefit of alleviating CNS diseases with a neuro-immune component.

The targeting of the brain immune system is a moredirect approach for the development of therapeutics forneurodegenerative diseases; however, this approach facesnumerous challenges. As mentioned previously, inflamma-tion has both beneficial and deleterious consequences and isdetermined by the magnitude and duration of inflammationsuch that high levels of inflammation or a protractedinflammatory state may overcome the beneficial effects ofinflammation. Greater understanding of the mechanismsrelated to acute inflammation and its beneficial effects canhelp guide pharmacotherapeutic strategies aimed at thepro-inflammatory processes involved in repair of CNSinjury such as the removal of toxic proteins, the increasedproduction of growth factors, and the clearance of inhibi-tory matrix proteins conducive for repair processes. On theother hand, chronic stimulation of the immune system hasneurodegenerative effects. Therefore, a major focus shouldbe directed towards selective suppression of neural mech-anisms involved in chronic inflammation, such as theinhibition of excessive glial cell activation (Nagatsu et al.2000), in a manner that does not cause a general weakeningof the immune system. This is exemplified by drugdevelopment efforts using animal models that are focusedon the suppression of inflammation for the ameliorationof the progressive degeneration observed in PD. Immuno-suppressants, immunophilin ligands, and COX-2 inhibitorshave shown some neuroprotective activity in animal modelsof PD but have met with limited success in human clinicaltrials (Gold and Nutt 2002). Regardless, knowledge andcharacterization of pharmacological agents with demon-strated success in animal models can provide important newdirections for the design of drugs with efficacious anti-inflammatory and neuroprotective properties. Along theselines, chemical modification of the semisynthetic tetracylineantibiotic and anti-inflammatory agent, minocyline, whichreadily crosses the BBB, is being explored to augment itsselectivity and efficacy (Kim and Suh 2009).

Additional therapeutic directions that are being taken arerelated to immune suppression via cell–cell contact or theproduction of anti-inflammatory cytokines such as TGFβ,IL-4, and IL-10. With regard to cell–cell contact, thepresence of neurons can reduce the activity of glial cellsand decrease the expression of glial fibrillary acid protein(GFAP), a marker of reactive astrocytes and inflammation.The mechanism for the cell–cell contact is through theexpression of neural cell adhesion molecule (NCAM).Moreover, the application of NCAM or NCAM-mimeticpeptide (Downer et al. 2009) is anti-inflammatory and thus


illustrates a potential pharmacological agent for immunesuppression.

Another possible treatment for inflammation-inducedneurodegenerative disease is the development of drugs thatspecifically block the inhibition of neurogenesis by cyto-kines, such as TNFα, IL-6, and IL-18, without preventingthe stimulatory effects of inflammation on neurogenesis. Arelated approach is the exogenous implantation of neuralprogenitor cells, but the success of this method relies on theability of the transplanted cells to differentiate into newneurons, integrate into the CNS circuitry, function properly,and survive.

Conclusion

In conclusion, broadening and expanding the depth of ourknowledge through research that bridges and integrates thedisciplines of pharmacology, neuroscience, and immunologywill markedly increase options for the development oftherapeutic compounds. More specifically, it is becomingclear that research in neuroscience can contribute to andbenefit from the convergence of evidence provided byinterdisciplinary research in immunology and pharmacologywith the benefit of therapeutic gain for the treatment of avariety of disease states and co-morbid conditions. Theconvergence of neuroscience, immunology, and pharmacologyis exemplified by the emerging interdisciplinary field ofneuroimmune pharmacology and has improved our under-standing of basic neurobiological processes and neurologicaldisease states with the exciting potential for the development ofnovel pharmacotherapies.

Disclaimers Neither author has any conflicts of interest.

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Neuroimmune Pharmacology from a Neuroscience Perspective