Neuroimmune Pharmacology from a Neuroscience Perspective

Abstract

The focus of this commentary is to describe how neuroscience, immunology, and pharmacology intersect and how interdisciplinary research involving these areas has expanded knowledge in the area of neuroscience, in particular. Examples are presented to illustrate that the brain can react to the peripheral immune system and possesses immune function and that resident immune molecules play a role in normal brain physiology. In addition, evidence is presented that the brain immune system plays an important role in mediating neurodegenerative diseases, the aging process, and neurodevelopment and synaptic plasticity. The identification of these mechanisms has been facilitated by pharmacological studies and has opened new possibilities for pharmacotherapeutic approaches to the treatment of brain disorders. The emerging field of neuroimmune pharmacology exemplifies this interdisciplinary approach and has facilitated the study of basic cellular and molecular events and disease states and opens avenues for novel therapies.

Introduction

A burgeoning research field in the area of neuroscience is neuroimmunology and the pharmacology of immune function within the brain. Historically, research in neuroscience and immunology progressed independently for many years, due primarily to four reasons described by Chang et al. (2009). First, the knowledge and presence of the blood–brain barrier (BBB) was thought to exclude most immune components. Second, the expression of the major histocompatibility complex (MHC), which presents antigen to T-lymphocytes, is suppressed in the brain except in the presence of an immune stimulus. Third, very few lymphocytes are present in the brain, and those that infiltrate the brain undergo apoptosis. Fourth, the production of proinflammatory cytokines is limited in the brain. It is now known that the two systems are integrated in that the brain has immune function and interacts with the peripheral immune system. The following review will summarize and comment on the current literature related to the intersection of neuroscience, immunology, and pharmacology. The integration of these fields of research will be reviewed within the context of normal brain function, disease states, and possible pharmacotherapeutic intervention strategies (Table 1).

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

The brain and immune function

The brain has resident cells capable of producing molecules that participate in the immune response against pathogens or in response to injury. This overall response is characterized by inflammation, mediated by both glial cells and neurons, and mimics the innate immune response in the periphery.

Microglial cells are the resident brain macrophages and are the initial responders to an immunological challenge in the brain. Upon activation, microglia will produce immune molecules in response to a foreign pathogen or neuronal insult and facilitate the recruitment of other immune cells. These molecules include cytokines, chemokines, complement proteins, and upregulated cell surface receptors, such as cytokine receptors and toll-like receptors (TLR) (Chang et al. 2009; Lucin and Wyss-Coray 2009). TLRs in the brain are the initial responders to an infectious agent, similar to their function in the periphery, and are known for their innate ability to recognize pathogen-associated molecular patterns (PAMPs) expressed by microorganisms. In addition, endogenous ligands for the TLRs have been discovered and are thought to play a role in some neurodegenerative processes (Walter et al. 2007; see below). Signaling through the TLRs is very similar to the IL-1 receptor family, leading to the downstream activation of the transcription factors NFκB and AP1. Similarly, signaling through the tumor necrosis factor (TNF) receptor family can activate NFκB and AP1. In contrast, the gp130 receptor family signals through the MAPK pathways to activate AP1, but not NFκB. Both NFκB and AP1 can be activated by free radicals and cellular stress and promote transcription of a variety 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 also participate in the immune response by producing and responding to these immune molecules.

Neurons exhibit a marked sensitivity to inflammatory stimuli such that cytokines upregulate inducible nitric oxide synthase (iNOS) and phagocytic NADPH oxidase (PHOX) in the brain. If unchecked, these stimuli could lead to neuronal death via oxidative damage (Brown 2007). Therefore, the inflammatory immune response in the brain under normal conditions must be highly regulated to minimize neuronal damage. The stringent regulatory mechanisms for the inflammatory response in the brain are the reasons for the historical and erroneous viewpoint that the brain and immune system do not interact. As stated above, these include (1) the presence of the BBB and other endogenous factors, which results in the exclusion of the majority of the peripheral immune systems components (Hickey et al. 1991); (2) the suppression of antigen presentation and suppression of MHC expression (Neumann et al. 1998); (3) the rapid apoptosis of the minimal lymphocytes (B cells and T cells), which gain access to the brain (Bauer et al. 1995); and finally, (4) the limited ability for the production of proinflammatory cytokines, such as TNFα and IL-1β (Perry et al. 1993). A variety of neurotransmitters and neurohormones are responsible for some of these immunosuppressive events (Lucin and Wyss-Coray 2009; Chang et al. 2009). For example, norepinephrine (NE), vasoactive intestinal peptide (VIP), and glutamate are capable of suppressing MHC class II expression in astrocytes (Frohman et al. 1988; Lee et al. 1992) and NE, dynorphin, and 17β-estradiol are all capable of suppressing microglial activation and the release of 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 minimal immune activation and a limited presence of immune molecules. However, low levels of immune molecules are required in the brain for protection against foreign agents, are necessary for normal brain development, and modulate synaptic plasticity in the mature brain. This duality of roles in mediating normal brain function and neuronal damage, where too much of a good thing can be bad, renders it necessary that the immune response in the brain be tightly regulated.

Immune molecules in normal brain physiology

Despite the paucity of immune activation and sparse presence of immune molecules in the adult brain under basal conditions, there is increasing evidence for the role of immune molecules in brain development and synaptic plasticity (Boulanger 2009). More specifically, cytokines and chemokines are involved in neuronal differentiation and migration, as well as the regulation of cell survival during development. For example, transforming growth factor beta (TGFβ) is required for differentiation of progenitor cells into tyrosine hydroxylase (TH) positive dopaminergic neurons in the ventral midbrain (Roussa et al. 2006). The chemokine CXCL12 (SDF-1) and its receptor CXCR4 are important for the migration of GABAergic interneurons from the ganglionic eminences into the cortex during embryogenesis (Stumm et al. 2003). Furthermore, the gp130 family cytokines, specifically cardiotrophin-1 (CT-1) and leukemia inhibitory factor (LIF), regulate motor neurons during development and function to maintain motor axons later in life, respectively (Holtmann et al. 2005). These are only a few of several cytokines and various immune proteins that are involved in synaptic plasticity in the developing and mature brain. Therefore, as our knowledge of immune factors expands, a growing list of mediators that interact to control plasticity and development, which extends beyond growth factors alone, must be considered.

The brain undergoes two main types of plasticity: activity-dependent and homeostatic plasticity. The same immune proteins seem to play a similar role in both types of plasticity 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 of synapses in the connections between the retinal ganglion and the dorsal lateral geniculate nucleus (Huh et al. 2000; Stevens et al. 2007). In the adult brain, MHCI also facilitates activity-dependent synaptic plasticity in the adult hippocampus (Huh et al. 2000). Pentraxins are proteins involved in the humoral immune response. They are produced by neurons in the brain, function to regulate the number of excitatory synapses in the mature brain, and are required for normal developmental synapse remodeling (Xu et al. 2003). These examples highlight the close similarities between the roles of these immune molecules in central nervous system (CNS) development, where they function to remove unwanted synapses, and in the peripheral immune response, where they destroy and remove unwanted cells. In addition, these mechanisms for synapse elimination could have important implications for the loss of synapses in neurodegenerative diseases, where these same molecules of the innate immune response are upregulated in neurons.

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

Further investigation is warranted to improve our understanding of these immune proteins and their roles in the brain. Regardless, knowledge of the brain immune system has markedly improved our understanding of normal brain function and development, as well as the response of the brain to insults, injury, and its ability to attempt repair. The following text will attempt to illustrate how information in the field of immunology has expanded our knowledge of neurodegenerative diseases and has provided new opportunities for the development of pharmacotherapeutic agents for the treatment of neurodegenerative diseases.

Neuroinflammation in neurodegenerative diseases

As discussed above, the nervous and immune systems are closely intertwined. An additional example of this interaction is the prominent role the immune system plays in neurodegenerative diseases. The responses of the nervous system to infection and injury are essentially under the control of the peripheral and brain immune systems. Although it is not clear if peripheral immune factors can influence neurodegenerative disease, emerging evidence suggests that altering peripheral inflammation during neurodegenerative disease can alter disease course. In addition, the brain can also react with its own immune response through its activation by the predominant immune cells of the brain, microglia. Microglia are sentinels of the milieu of the brain and produce factors that affect other glial cells, such as astrocytes, as well as neurons. The invasion of a pathogen or the initial appearance of tissue damage prompts the immune system to engage in repair (e.g., phagocytosis) and then subside once the reparative or protective process has been completed. However, under certain conditions when the damaging stimulus persists, the sustained inflammation may result in the production of neurotoxic mediators and eventual neuronal damage, such as that which is evident in neurological diseases and in response to various insults, such as mechanical injury and drugs of abuse.

Multiple sclerosis

Multiple sclerosis (MS) is a well known neurodegenerative disease characterized by an autoimmune response resulting in inflammation, demyelination, and axon degeneration. Lesions evident in MS are marked by an increase in microglia and astrocytes, as well as the infiltration of the brain and spinal cord matter by lymphocytes and antigen presenting cells from the plasma (Lassmann et al. 2001). In particular, there is a deposition of antibodies and complement proteins around the lesions of demyelination resulting from the activation of both the innate and acquired immune systems. T-cells recognize myelin basic protein which is autoantigenic and stimulates the production of cytokines to activate NFκB and AP1. In the presence of IL-6 and TGFβ, T cells will express retinoic acid receptor-related orphan receptor γt and differentiate into Th17 cells that secrete IL-17 and TNFα to produce damage to myelin (Glass et al. 2010). The further progression of MS is mediated by T and B lymphocytes, which amplify the autoimmune responses.

Alzheimer’s disease

Examples of inflammatory responses in the brains of Alzheimer’s patients include astrogliosis around senile plaques and proinflammatory mediators including 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 in conjunction with the activation of microglia that may be precipitated by Aβ aggregation, the classic biomarker of the disease. The resultant increase in these inflammatory mediators can promote neuronal death evident in Alzheimer’s disease (AD) (Akiyama et al. 2000). The detection of Aβ by microglia and astrocytes may occur through the activation of TLR 2 and 4 to stimulate transcription factors (NFκB and AP1) and activate inflammatory response genes (Walter et al. 2007). Other receptors that have been shown to mediate the inflammatory response to Aβ are the receptor for advanced glycoxidation end-products (RAGE) and NOD-like receptors (NLR), both of which are expressed by microglia, cause an increase in pro-inflammatory factors, and stimulate apoptosis (Yan et al. 1996; Halle et al. 2008). Although the roles of Aβ and Aβ aggregation in the initiation of inflammation remain unclear, it is evident that proinflammatory mediators can amplify the immune response and cause a feed-forward cycle among microglia, between microglia and astrocytes, and between microglia and neurons. For example, cytokines from microglia can activate secretase activity in neurons (Sastre et al. 2008) and cause cell death, while TNFα and IL-1β released by microglia can activate astrocytes and cytokine release by astrocytes can activate microglia.

Parkinson’s Disease

Although the loss of dopaminergic neurons is the hallmark pathological feature of PD, microglial activation and infiltration by astroglia and lymphocytes are also prominent in the substantia nigra of PD patients (McGeer et al. 1988). In parallel with Aβ aggregation in AD, aggregation of α-synuclein has been shown to damage dopamine cells. It is this aggregation of α-synuclein that can activate microglia and stimulate the release of TNFα and IL-1β, as well as reactive oxygen species, and nitric oxide to modulate and cause cell death (Hirsch and Hunot 2009). An interesting observation is that the increased expression of genes encoding these proinflammatory cytokines reside in glial cells within in the lateral region of the substantia nigra, and it is the lateral region that degenerates before other subregions of the substantia nigra (Chung et al 2005). These findings lend credence to the hypothesis that dysregulation of glia through immune responsivity is a pathogenic mechanism underlying PD. Moreover, using positron emission tomography (PET), PD patients exhibit markedly elevated inflammation in several brain regions, including the basal ganglia, and that the degree of elevation is irrespective of the number of years with the disease (Gerhard et al. 2006). Therefore, these results indicate that neuroinflammation can occur coincident with the ongoing loss of dopamine neurons and perhaps can appear early in the disease process. In fact, the strongest evidence that neuroimmune inflammation plays a role in the pathogenesis of the disease is that dopamine neurons are exquisitely sensitive to cytokines (McGuire et al. 2001). This may be due to the fact that dopamine neurons contain iron and are subject to oxidative processes and hydroxyl radical production resulting from the Fenton reaction. This predisposition of dopamine neurons may therefore render them vulnerable to inflammatory stimuli, infections, and environmental toxins that can stimulate the neuroimmune response and microglial activation to initiate a feed-forward process. Regardless of whether inflammation is the initial cause of disease, the self-perpetuating process of cytokine release, microglia activation, neuronal death, and further activation and clustering of microglia around the increase in cellular debris promotes the progressive degeneration of dopamine neurons that is characteristic of PD.

Traumatic brain injury and infections

The neuroinflammatory responses to traumatic brain injury (TBI) and infections are triggered by several factors described above that are released from astrocytes and microglia. These include cytokines, interlukin-1 and TNFα, chemokines, and adhesion molecules. A major driving force in the inflammatory response to TBI is the activation of cytokine genes (Tchelingerian et al. 1994) that promote the release of TNFα, IL-1, and IL-6, leading to the aggravation of brain injury. Supporting evidence for their role in the exacerbation of TBI and secondary brain injury is provided by evidence showing that specific cytokines can exacerbate brain damage and that specific cytokine antagonists can reduce ischemic brain damage and improve neurological outcome (Lucas et al. 2006; Ghirnikar et al. 1998; Rothwell and Luheshi 2000). TNFα is present in the CSF and serum of TBI patients, which, in turn, has been shown to increase the synthesis of several other cytokines, upregulate the expression of chemokines, promote astrogliosis, and increase metalloproteinase activity that can break down the cellular matrix and increase the permeability of the BBB (Shohami et al. 1999).

Similar to TNFα, IL-1β is involved in TBI and acts synergistically with TNFα to contribute to brain injury and infection. IL-1β can stimulate TNFα and IL-6 production by astrocytes, whereas antibodies to IL-1α and β (Lu et al. 2005) or the administration of IL-1R antagonist (Tehranian et al. 2002) can attenuate the neurotoxic effects of TBI. In addition, blockade of pro-IL-1β converting enzyme reduced brain damage to ischemia. Along similar lines, bacterial infection with endotoxins such as lipopolysaccaride upregulates mRNA of IL-1R1 subtype and triggers microglia to synthesize neuroinflammatory mediators (Pournajafi Nazarloo et al. 2003; Cai et al. 2003).

Although a wealth of evidence supports the damaging effects of immunoinflammatory reactions, the role of inflammation and its cellular mediators can also play a role in the reparative process. Reactive astrocytes can produce neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic growth factor (BDNF) and pluripotent proteins such as fibroblast growth factor (FGF), S100β and ciliary neurotrophic factor (CNTF), which can stimulate axonal growth and promote regeneration (Myer et al. 2006). TGF-β, IL-10, and IL-4 are examples of endogenous anti-inflammatory mediators that can inhibit the production of proinflammatory cytokines and MHC class II antigens (Kadhim et al. 2008; Cederberg and Siesjö 2010). These endogenous anti-inflammatory mediators are thought to limit the degree of damage in response to TBI or infection, restrict the extent of secondary neural damage, and increase the rate of subsequent repair and recovery (Kadhim et al. 2008). The activation of these anti-inflammatory mediators is controlled possibly by the differential activation of signaling pathways and the receptor interactions within local microenvironment of the damaged tissue.

Drugs of abuse and neurotoxins

Illicit drugs such as psychostimulants, cannabis, and opiates have various sites of 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 both suppress the peripheral immune response (Cabral 2006) but have opposing effects on neuroinflammation.

Neurotoxic amphetamines, including d-amphetamine, methamphetamine (Meth) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), produce neuroinflammation through microglial activation and increases in the proinflammatory cytokines, IL-β, and TNFα (Thomas et al. 2004; Orio et al. 2004; Gonçalves et al. 2008). It remains unclear, however, whether neuroinflammation is a cause for the neuronal damage observed with these drugs or a consequence of the damage in order to repair the brain after exposure to the drugs.

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

In contrast to the inflammation produced in the CNS, psychostimulants suppress the peripheral immune system and increase the susceptibility to infection (Cabral 2006) and comorbidity of drug abuse and human immunodeficiency virus (HIV) infection. HIV is a retrovirus that infects immune cells and ultimately leads to destruction of the host immune system. In late stages of HIV infection, patients suffer from dementia. Although it is unclear exactly what mechanisms are involved in the neuronal damage, it is evident that immune molecules play a role. In the late stages of HIV infection, elevated levels of a variety of cytokines, including TNFα and IL-1β, and chemokines, specifically monocyte chemoattractant protein-1 (MCP-1/CCL2), are detected in serum of HIV patients. Combined exposure to Meth and HIV infection results in the potentiation of neuroinflammatory response and enhanced damage in the brain (Maragos et al. 2002; Flora et al. 2003; Reiner et al. 2009).

Matrix metalloproteinase (MMP) expression and activity is upregulated in response to the proinflammatory cytokine production, and the activities of these proteases have been associated with increased BBB permeability. An in vitro study illustrated that an incubation of HIV-infected monocytes/macrophages with endogenous inhibitors of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, attenuated the increased permeability of endothelial cell monolayers to radioactive labeled albumin. (Dhawan et al. 1995) Furthermore, human neuronal cultures exposed to Meth in combination with the HIV protein Tat produced an enhanced release of MMP-1 and the MMP activator, urokinase plasminogen activator (uPA) (Conant et al. 2004), suggesting that the combined exposure to Meth and HIV enhances neuroinflammation and the eventual breakdown of the BBB. The chemokine, MCP-1/CCL2, is also partially responsible for disrupting the BBB and facilitating the migration of HIV infected cells into the brain (Eugenin et al. 2006). Upon entry into the brain, the infected monocytes and macrophages release viral proteins, such as Tat, gp120, and gp41, activate the resident glial cells, and promote the production of inflammatory molecules in the brain; however, it remains unclear whether the viral proteins themselves or the over-activation of the immune response in the brain is responsible for damage.

In contrast to other drugs of abuse, cannabinoids are anti-inflammatory and capable of attenuating neural damage (Iuvone et al. 2009). Cannabinoids produce their actions primarily through the cannabinoid receptors, CB1 and CB2, though there has been some evidence of non-CB1 and non-CB2 actions, such as those through the peroxisome proliferator-activated receptors (PPARs) (Burstein 2005; O’Sullivan 2007; Sun et al. 2007). The CB1 receptor is prominent in the CNS on neurons, where its role is to alter neurotransmitter release, as well as on glia (Herkenham et al. 1990). A synthetic CB1 receptor agonist decreased hippocampal neuronal loss after transient global ischemia and reduced infarct volume after permanent focal ischemia in rats (Nagayama et al. 1999). Furthermore, CB1 receptor expression is significantly decreased in the brains of Alzheimer’s patients and a synthetic cannabinoid, WIN55,212-2, attenuated beta-amyloid-induced microglial activation, cognitive impairment, and loss of neuronal markers in rats (Ramírez et al. 2005). The CB2 receptor is primarily localized to cells of the immune system but has been identified in both glia and neurons (Gong et al. 2006). The major role of the CB2 receptor is the modulation of cytokine release. Activation of the CB2 receptor in microglial cultures, suppresses IFNγ-induced microglial activation and production of cytokines and nitric oxide (Ehrhart et al. 2005). A third site of action for cannabinoids in the brain is the PPAR, nuclear receptors that have anti-inflammatory properties upon activation (Daynes and Jones 2002). N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound, provided neuroprotection against middle cerebral artery occlusion in wild-type but not PPARα-deficient mice, via an increase in IκB and decrease in COX-2 (Sun et al. 2007). Although cannabinoids are anti-inflammatory, the challenge is the identification of a cannabinoid compound that is anti-inflammatory but lacks psychotropic effects. Further understanding of the cannabinoid system may provide new therapeutic targets for the treatment of neurodegenerative diseases.

In addition to HIV, other toxins are known to cause inflammation and neurodegeneration. As noted above, inflammation plays a prominent role in the pathogenesis of Parkinson’s disease. The late onset and slowly progressive nature of the disease has implicated early life exposure to environmental toxins such as agrochemicals and pesticides as risk factors for the disease (for review, see Liu et al. 2003). Some of these toxins are known to activate brain immune cells such as microglia and astrocytes to initiate a self perpetuating cycle of neuroinflammation, brain injury, further inflammation, and progressive neurodegeneration.

Neuroinflammation in aging

As several neurodegenerative diseases such as PD and AD are age-related disorders, it serves to reason that the normal process of aging may be superimposed on the disease process to exacerbate neuroinflammatory mechanisms and promote cell loss. In fact, there is a substantial amount of evidence that neuroinflammation is associated with aging and sensitizes the brain to the effects of infection or stress.

The aged brain exhibits increased numbers of activated microglia, complement proteins, and primed microglia (Lucin and Wyss-Coray 2009) that permit a greater cytokine release upon activation (Streit et al. 2008). Moreover, there are increased levels of IL-6 in the plasma of the elderly, and these levels are associated with an increased risk of cognitive impairment (Weaver et al. 2002). Conversely, reductions in the levels of anti-inflammatory cytokines, such as IL-10, have been observed in the aged brain, which may render the aged individual more susceptible to peripheral immune activation of the brain. In fact, a reduction in IL-10 is associated with an increased vulnerability to neurodegenerative diseases, including Alzheimer’s (De Luigi et al. 2001). Consistent with this finding is a study showing that neuroinflammation produced by peripheral immune activation exacerbates cognitive dysfunction in aged animals (Chen et al. 2008). Furthermore, aged animals appear to be more susceptible to the deleterious effects of stress through the sensitization of neuroinflammatory mechanisms.

Stressors are well known to induce proinflammatory cytokines in the brain and can sensitize the immune response to an immunological stimulus and exacerbate neuroinflammation. In fact, mild repeated stressors exacerbate neuroinflammation in aged mice and produce more deficits in learning and memory compared to younger adult mice (Lupien et al. 2007). Thus, aging is associated with increased neuroinflammation that may sensitize the aged brain to infection or stress and compromise the ability of the aged individual to cope and recover from disease and stress.

Neuroimmune effects on neurogenesis

Neuroimmune inflammation can alter neurogenesis in a variety of ways. In general, inflammation is known to stimulate neurogenesis. Thus, neuroinflammatory responses in 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 numerous chemokines such as stromal cell-derived factor-1α (SDF-1α) and MCP-1 induce the proliferation and/or migration of neural progenitor cells (Whitney et al. 2009), most likely through chemokine receptors expressed in neural progenitor cells (Ji et al. 2004).

Not only does inflammation stimulate neurogenesis, it can also suppress neurogenesis. This duality of effect is dependent on the means by which microglia, macrophages, and/or astrocytes are activated and whether the inflammation is acute or chronic. For example, microglia activated by proinflammatory cytokines inhibit neurogenesis, but microglia 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 inflammation can promote neurogenesis to replace the damaged neuron; however, continued recruitment of microglia and peripheral macrophages by chemokines to the site of inflammation can result in a chronic inflammatory response and produce a feed-forward process leading to reduced survival of newly born cells and neuronal damage (Whitney et al. 2009).

Pharmacology of neuroimmune responses

Understanding of the pharmacology of immune responses in the brain has lagged behind the contribution of pharmacology to the understanding of neurological and peripheral immunological processes. This is due primarily to the traditional mindset that the brain is an immune privileged organ. As noted above, this historical viewpoint is no longer true and is evidenced by the considerable crosstalk between the immune and nervous systems and a wealth of emergent information, indicating that the peripheral immune system has the ability to modulate multiple brain functions. Therefore, targeting the peripheral immune system for the treatment of neuroimmune disorders in the brain cannot be discounted as a viable pharmacotherapeutic approach. It will be important to determine which types of chronic peripheral inflammatory diseases (i.e., arthritis, inflammatory bowel disease, infections, etc.) exacerbate certain neurodegenerative diseases. Thus, treatments for these peripheral disorders may have the added benefit of alleviating CNS diseases with a neuroimmune component.

The targeting of the brain immune system is a more direct approach for the development of therapeutics for neurodegenerative diseases; however, this approach faces numerous challenges. As mentioned previously, inflammation has both beneficial and deleterious consequences and is determined by the magnitude and duration of inflammation such that high levels of inflammation or a protracted inflammatory state may overcome the beneficial effects of inflammation. Greater understanding of the mechanisms related to acute inflammation and its beneficial effects can help guide pharmacotherapeutic strategies aimed at the pro-inflammatory processes involved in repair of CNS injury such as the removal of toxic proteins, the increased production of growth factors, and the clearance of inhibitory matrix proteins conducive for repair processes. On the other hand, chronic stimulation of the immune system has neurodegenerative effects. Therefore, a major focus should be directed towards selective suppression of neural mechanisms involved in chronic inflammation, such as the inhibition of excessive glial cell activation (Nagatsu et al. 2000), in a manner that does not cause a general weakening of the immune system. This is exemplified by drug development efforts using animal models that are focused on the suppression of inflammation for the amelioration of the progressive degeneration observed in PD. Immunosuppressants, immunophilin ligands, and COX-2 inhibitors have shown some neuroprotective activity in animal models of PD but have met with limited success in human clinical trials (Gold and Nutt 2002). Regardless, knowledge and characterization of pharmacological agents with demonstrated success in animal models can provide important new directions for the design of drugs with efficacious anti-inflammatory and neuroprotective properties. Along these lines, chemical modification of the semisynthetic tetracyline antibiotic and anti-inflammatory agent, minocyline, which readily crosses the BBB, is being explored to augment its selectivity and efficacy (Kim and Suh 2009).

Additional therapeutic directions that are being taken are related to immune suppression via cell–cell contact or the production of anti-inflammatory cytokines such as TGFβ, IL-4, and IL-10. With regard to cell–cell contact, the presence of neurons can reduce the activity of glial cells and 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 the expression of neural cell adhesion molecule (NCAM). Moreover, the application of NCAM or NCAM-mimetic peptide (Downer et al. 2009) is anti-inflammatory and thus illustrates a potential pharmacological agent for immune suppression.

Another possible treatment for inflammation-induced neurodegenerative disease is the development of drugs that specifically block the inhibition of neurogenesis by cytokines, such as TNFα, IL-6, and IL-18, without preventing the stimulatory effects of inflammation on neurogenesis. A related approach is the exogenous implantation of neural progenitor cells, but the success of this method relies on the ability of the transplanted cells to differentiate into new neurons, integrate into the CNS circuitry, function properly, and survive.

Conclusion

In conclusion, broadening and expanding the depth of our knowledge through research that bridges and integrates the disciplines of pharmacology, neuroscience, and immunology will markedly increase options for the development of therapeutic compounds. More specifically, it is becoming clear that research in neuroscience can contribute to and benefit from the convergence of evidence provided by interdisciplinary research in immunology and pharmacology with the benefit of therapeutic gain for the treatment of a variety of disease states and co-morbid conditions. The convergence of neuroscience, immunology, and pharmacology is exemplified by the emerging interdisciplinary field of neuroimmune pharmacology and has improved our understanding of basic neurobiological processes and neurological disease states with the exciting potential for the development of novel pharmacotherapies.