The role of the innate immune system in psychiatric disorders

Molecular and Cellular Neuroscience 53 (2013) 52–62

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Review

The role of the innate immune system in psychiatric disorders Kenneth A. Jones ⁎, Christian Thomsen 1 Lundbeck Research USA, Neuroinflammation Drug Biology Unit 215 College Road, Paramus, NJ 07652, USA

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Article history: Received 20 April 2012 Accepted 4 October 2012 Available online 12 October 2012 Keywords: Inflammation Neuroinflammation Microglia IL-1β TNFα Depression PTSD Bipolar disorder Biomarker Cytokine

a b s t r a c t There is by now substantial clinical evidence for an association between specific mood disorders and altered immune function. More recently, a number of hypotheses have been forwarded to explain how components of the innate immune system can regulate brain function at the cellular and systems levels and how these may underlie the pathology of disorders such as depression, PTSD and bipolar disorder. In this review we draw reference to biochemical, cellular and animal disease models, as well as clinical observations to elucidate the role of the innate immune system in psychiatric disorders. Proinflammatory cytokines, such as IL-1β IL-6 and TNFα, which feature prominently in the immune response to pathogen in the periphery, have unique and specific actions on neurons and circuits within the central nervous system. Effects of these signaling molecules on neurotransmission, memory, and glucocorticoid function, as well as animal behaviors such as social withdrawal and fear conditioning relevant to psychiatric disorders are elucidated. Finally, we highlight future directions for studies, including the use of peripheral biomarkers, relevant for developing new therapeutic approaches for treating psychiatric illnesses. This article is part of Special Issue entitled 'neuroinflammation in neurodegeneration and neurodysfunction'. © 2012 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cytokines and cellular mediators of neuroinflammation—peripheral/central interactions Major depressive disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . Immune response to stress . . . . . . . . . . . . . . . . . Microglia . . . . . . . . . . . . . . . . . . . . . . . . . Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . Pro-inflammatory cytokines and depression . . . . . . . . . Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . Post-traumatic stress disorder . . . . . . . . . . . . . . . . . . . . . . . . . Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical studies and biomarkers . . . . . . . . . . . . . . . . . . . Bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: PTSD, post-traumatic stress disorder; IL-1β, interleukin-1beta; IL-6, interleukin-6; TNFα, tumor necrosis factor alpha; IFNα, interferon alpha; TLR, toll-like receptor; LPS, lipopolysaccharide; CRP, C-reactive protein; NFкβ, nuclear factor kappa beta; HPA, hypothalamic-pituitary axis; MDD, major depressive disorder; SSRI, selective serotonin reuptake inhibitor; CNS, central nervous system; MC4, melanocortin receptor 4; BDNF, brain derived neurotrophic factor; IDO, indoleamine 2,3-dioxygenase; NMDA, N-methyl-D-aspartate; HPA, hypothalamic pituitary axis; PBMC, peripheral blood mononuclear cells; HDAC, histone deacetylase; TREM-1, triggering receptor expressed on myeloid cells-1. ⁎ Corresponding author at: Forest Research Institute, Harborside Financial Center, Plaza V, Jersey City, NJ 07311, USA. Fax: +1 201 427 8200. E-mail address: [email protected] (K.A. Jones). 1 Present address: H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. 1044-7431/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.mcn.2012.10.002

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Future directions — novel treatment opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Depression and other mood disorders are among the most common diseases worldwide and are associated with a tremendous burden to the people affected as well as high rates of suicide. Despite the fact that there has been substantial effort to develop new drugs and that modern, selective antidepressants represent significant therapeutic progress, there are still considerable unmet needs. To address those needs particularly related to therapeutic non-responders a rational approach would be to search for novel mechanisms of action. Most antidepressants function by modulating serotonergic and/or noradrenergic neurotransmission, and while this is an important mechanism therapeutically, its role in disease etiology is yet unclear. As a result, the identification of additional pathophysiological changes associated with depressive disorders is an important goal. Growing evidence points to a significant role for elements of the immune system to dramatically influence brain function in ways that are relevant to facets of psychiatric and neurological diseases. This review will not attempt to cover all psychiatric disorders but instead will focus on those, particularly depression, post-traumatic stress disorder, and bipolar disorder that appear to share manifestations of chronic maladaptive changes in central nervous system function by elements of the innate immune system (“neuroinflammation”). We will draw reference to biochemical, cellular, and animal disease models, as well as clinical observations to elucidate the role of the innate immune system in psychiatric disorders. Finally, we will point out potential new directions for future studies relevant for developing therapeutic approaches for treating psychiatric illnesses. Cytokines and cellular mediators of neuroinflammation—peripheral/ central interactions There is a growing appreciation of the profound interrelationship between the central nervous system (CNS) and immune systems, and this is perhaps best exemplified within the context of the innate immune system. In contrast to the more highly evolved adaptive

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immune system which is able to recognize and remember specific pathogens, and to mount stronger attacks each time the pathogen is encountered, the innate immune system is genetically encoded to stereotypically respond to specific signals derived from pathogens or other danger signals. These signals derive from common pathogens, such as bacterial cell wall components (lipopolysaccharides, LPS), and components from tissue damage, such as ATP, uric acid, and heat shock proteins. The recently discovered family of toll-like receptors (TLRs — Gay and Keith, 1991) binds some of these components and initiates a signal transduction cascade which results in the release of pro-inflammatory cytokines and chemokines in order to neutralize pathogen and initiate tissue repair. Of the inflammatory mediators, the most well-studied are the cytokines interleukin 1beta (IL-1β, interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα). All of these are released by macrophages, other peripheral immune cells, and microglia, as part of the early acute phase reaction which provides defense against invading pathogens. These cytokines are robustly stimulated by molecules associated with pathogens, such as LPS and viral nucleic acids, that bind to TLRs and activate the NFкβ pathway (Fig 1). IL-1β is considered the “master cytokine” because its release is an early event that triggers release of others components of the acute phase response, including IL-6 (Dinarello, 2009). The production, maturation and release of IL-1β are controlled by dual pathways that involve TLRs, which activate transcription, and the interaction of the P2X7 receptor, pannexin-1 and caspase-1, which process the mature form of IL-1β prior to release (Abbracchio et al., 2009; Di Virgilio, 2007). These cytokines also serve to signal tissue injury, both locally, in the case of microglia, and systemically, in the case of IL-6. Major sources of IL-6 are liver and muscle as a result of hepatotoxicity and muscle damage, respectively. Strenuous exercise also elevates IL-6, and as a result it can show great variability as a plasma biomarker. TNFα, together with IL-1β and IL-6 have well described actions on the hypothalamus including induction of fever, suppression of appetite, and stimulation of the hypothalamic pituitary axis (HPA) to release corticotropin-releasing factor (Goshen et al., 2008; Goshen and Yirmiya, 2009; Layé et al., 2000). TNFα in particular is involved in

Fig. 1. Pathways for regulation and secretion of IL-1β and other neuroactive cytokines and their effects on the nervous system. Regulation of IL-6, TNFα and IL-1β is primarily via the NFкβ pathway through transcriptional activation. Inactive pro-IL-1β (as well as pro-IL-18 — not shown) requires further processing by the inflammasome component caspase-1. Endogenous stimulants include extracellular ATP and bacterial LPS. There are many other endogenous and exogenous inflammatory mediators that cause acute inflammation via other TLR subtypes and additional components of the inflammasome (not shown). See text for details on specific roles of each cytokine on cellular and behavioral effects.

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synaptic scaling whereby low extracellular glutamate triggers release of the cytokine from astrocytes and promotes the surface expression of postsynaptic glutamate receptors (Beattie et al., 2002). Additionally, the cytokine upregulates presynaptic function by augmenting vesicular release of glutamate from astrocytes which activates presynaptic NMDA receptors (Santello and Volterra, 2012). New fundamental roles for cytokines in normal brain function and in disease are being discovered at a rapid pace. In addition to the hypothalamus, cytokines can be produced in other brain regions, most notably the dentate gyrus of the hippocampus and amygdala. Receptors for IL-1β and other cytokines have typically been localized to these same regions (French et al., 1999; Frost et al., 2001). The source of these cytokines in the hypothalamus and other brain structures depends on the nature of the stimuli. There is in fact good evidence that they can originate both from the peripheral circulation following induction by LPS, as well as from local synthesis in neurons and glia (reviewed in Dantzer et al., 2008; Raison et al., 2006). Peripherally induced cytokines, particularly IL-1β and TNFα, can enter the brain by an active transport system (Skinner, et al., 1993; Gutierrez, et al., 2009). Once in the brain, these cytokines induce their own synthesis (Layé et al., 1994; Pitossi et al., 1997). As described in detail in subsequent sections, IL-1β, TNFα and IL-6 expression are also regulated via the centrally generated response to stress and activation of the HPA axis. It is the complex interplay between central and peripheral cytokines that ultimately influences the behavioral response to an environmental challenge. Microglia comprise about 10% of the cells in the brain and function as the resident immune sentinels. In contrast to their peripheral counterparts, macrophages which also stem from myeloid progenitor cells, microglia are relatively quiescent in their resting/surveillance state and have a variable rate of renewal. While the brain has been considered “immune-privileged” it has become increasingly apparent in the last decade that peripheral inflammation affects the CNS via several mechanisms. In addition to the cytokine-mediated neuroendocrine signaling through the adrenal glands as part of the HPA axis (Goshen and Yirmiya, 2009), diverse populations and phenotypes of CD4 (+) T cells signal with microglia and thereby affect their state of activation (Miller, 2010). However, since this review is focused on the role of the innate immune system in psychiatric disorders we will refer the reader to recent reviews on the possible roles of Th-cells and regulatory T-cells in mood disorders (Miller, 2010; Yirmiya and Goshen, 2011). Overall, in healthy brain, neuroinflammation is an acute process that is tightly controlled and has the purpose of initiation and resolution of inflammation, and repair of damaged cells. During development, microglia serve an important role in synaptic pruning which is very important for normal development of the central nervous system (Paolicelli et al., 2011). However, when inflammation becomes excessive or prolonged it becomes part of the pathological process and may exacerbate or be the underlying cause of disease. Major depressive disorder Preclinical studies Immune response to stress In the past several years it has become increasingly clear that the CNS both reacts to and produces pro-inflammatory cytokines. In terms of modeling the influence of inflammation on “mood” in rodents the most common feature is “sickness behavior” (Dantzer, 2001; Parnet et al., 2002) characterized by lethargy, decreased interest in surroundings, social isolation and reduced food and water intake (for review see Dantzer et al., 2008; Miller et al., 2009; Raison et al., 2006). These symptoms correlate to some extent with depression-like symptoms in humans. Common mediators of sickness behavior include the proinflammatory cytokines IL-1β, IL-6, TNFα,

and interferon gamma (IFN-γ). These cytokines can act either via the vagus nerve which senses visceral infection and transmits signals to nuclei in regions such as hypothalamus and amygdala, or by binding to the vascular endothelium and inducing the generation of central mediators such as prostaglandins, or finally by entering the brain directly as previously described. Several mechanisms have been proposed to induce depression-like states via inflammatory molecules such as prostaglandin E2, IL-1β IL-6 and TNFα (Dantzer, 2001). These proinflammatory mediators affect the known regulators of mood such as tryptophan, kynurenine and monoamines, as well as more directly via other mechanisms. Multiple labs have demonstrated that IL-1β in particular, has a key role as a stress-sensitive neurohormone (see for review Goshen and Yirmiya, 2009). Both acute and chronic stress in mice and rats result in anhedonic-like behaviors that are reversed by icv infusion of the potent, endogenous IL-1β receptor antagonist, IL-1Ra (Goshen et al., 2008; Koo and Duman, 2008). IL-1β levels are increased in hypothalamus and other brain areas following a period of intense stress (Nguyen et al., 2000). The release of IL-1β after stress may be responsible for reduced cognitive performance, a key residual symptom of depressed patients treated with selective serotonin reuptake inhibitors (SSRIs), as both exogenously added and stress-stimulated IL-1β decrease memory in the conditioned fear and water maze paradigms (Buchanan et al., 2008; Goshen et al., 2007; Pugh et al., 1999). These effects on memory do not appear to be due to non-specific neurotoxicity since they are reversed by α-melanocyte stimulating hormone through activation of melanocortin receptor 4 (MC4) receptors (Gonzalez et al., 2009). Hippocampal neurogenesis and brain levels of the brain derived neurotrophic factor (BDNF) are thought to be mechanistically linked to depressed-like phenotypes in animal models. Two independent groups demonstrated that the anti-neurogenic action of stress is ablated in mice lacking the receptor for IL-1β (IL-1RI) and is greatly inhibited in wild-type animals by administration of IL-1Ra (Goshen et al., 2008; Koo and Duman, 2008). Other actions of IL-1β or TNFα that are consistent with their role in depression-related circuitry are inhibition of expression of both BDNF and the clock gene per3, (Cavadini et al., 2007; Barrientos et al., 2004). A member of the S100 family of proteins, p11 has been shown to be a key regulator of depressive-like states and antidepressant responses in several rodent models (Svenningsson and Greengard, 2007). Transgenic mice lacking p11 display a depressive-like phenotype and conversely p11 overexpressing mice display antidepressant-like behaviors (Svenningsson and Greengard, 2007). In contrast to the general notion that increased cytokines contribute to depression, these studies showed that cytokines and glucocorticoids upregulate the expression of p11 which in turn leads to modulation of 5-HT1B and 5-HT4 receptors and hence contribute to an anti-depressive phenotype following stress (Svenningsson et al., 2006). Subsequent studies led the authors to suggest that anti-inflammatories such as non-steroidal-anti-inflammatory drugs should be avoided if patients undergo treatment for depression with SSRI's (Warner-Schmidt et al., 2011). As discussed in the following section, this is in contrast to the clinical observations of anti-depressive effects of celecoxib and etanercept (Tyring et al., 2006; Muller et al., 2006) therefore further studies are warranted to finally conclude on this topic. Cytokines are implicated in HPA dysfunction associated with stress (Goshen and Yirmiya, 2009). IL-1β released within the hypothalamus stimulates secretion of corticotropin releasing hormone from the periventricular nucleus and ultimately release of glucocorticoids from the adrenal glands (Shintani et al., 1995). Normally, cortisol exerts a powerful negative feedback inhibition of cytokine production through inhibition of NFkβ and transcriptional suppression. During chronic stress, however, continuous release of IL-1α and IL-1β causes activation of p38 MAPK and jun-C kinase which inhibits the glucocorticoid response to corticosterone (Wang et al., 2004). This suppression of the glucocorticoid receptor negative

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feedback loop by interleukins may contribute to chronically elevated cortisol and inflammatory cytokines in depressed patients. Microglia Microglia are the main cellular players of the innate immune system in the brain and respond rapidly to stimuli such as infection or injury. When activated by damage they migrate to the site of infarct where they clear damaged neurons or other cellular components. However, in the non-injured brain the role of microglia is to provide surveillance of the environment and provide trophic support to healthy neurons (Kettenmann et al., 2011). However, stress-induced signaling molecules and glucocorticoids induce a pro-inflammatory response in microglia and this may lead to aberrant activation in the absence of infection or injuries (Nair and Bonneau, 2006). Since the HPA is activated in patients with depression, cortisol likely modulates microglia in stress-related brain disorders. Opposite effects of corticosterone has been observed dependent upon its site of interaction with either the low affinity glucocorticoid receptor or the high affinity mineralocorticoid receptor which may explain the opposite effects of corticosterone on the functions of microglial cells since the hormone acts as an inhibitor through glucocorticoid and a stimulator through mineralocorticoid receptors (Tanaka et al., 1997). It may be speculated that the acute activation of microglia via mineralocorticoid receptors enhances the trophic support to neurons whereas chronic stress combined with an impaired feedback loop from glucocorticoid receptors leads to sustained microglia activation which in this case would exacerbate the disease condition. Microglial activation by LPS or interferon gamma (IFN-γ) has been shown to be inhibited by a range of compounds with known antidepressant activity such as SSRIs, fluoxetine, citalopram, paroxetine, sertraline and the N-methyl-D-aspartate (NMDA) channel blocker, ketamine (Chang et al., 2009; Horikawa et al., 2010; Liu et al., 2011). These antidepressants also lead to a reduction in inflammatory mediators such as TNF-α and nitric oxide (NO). Various components of the sickness response induced by LPS can be ameliorated by treatment with minocycline or the angiotensin II receptor antagonist candesartan which blocks microglial activation (Benicky et al., 2011; Henry et al., 2008). It should be noted that opposite effects of SSRIs on microglia have been reported (at least in the substantia nigra) where they induce activation and down-regulate the activity of dopaminergic neurons (MacGillivray et al., 2011). Furthermore, the relevance of microglia activation to depression as induced by stimuli such as LPS can be questioned since this is associated with bacterial infection rather than a stress response. However, exposure to chronic stress causes microglial activation in the prefrontal cortex of rats and impaired spatial working memory (Nair and Bonneau, 2006). These effects are inhibited by minocycline, further emphasizing the role of microglia in deficits induced by chronic stress (Hinwood et al., 2011). Inflammation and stress-induced elevation of cytokines induce the upregulation of indoleamine 2,3-dioxygenase (IDO), an enzyme located in microglia that degrades tryptophan to kynurenine. Since L-tryptophan is the precursor for synthesis of 5-HT, induction of IDO through elevated cytokines might be expected to decrease the levels of 5-HT with a possible effect on mood (Miura et al., 2008). However a study of serotonin turnover in the brains of LPS-treated rats revealed no reduction of tryptophan or serotonin levels in brain even though tryptophan in the periphery was substantially reduced (O'Connor et al., 2009b), suggesting that L-tryptophan metabolism occurs in a separate pool in the CNS. The results argue that changes in metabolism induced by IDO upregulation in activated microglia have more to do with elevation of metabolites in the kynurenine pathway rather than reduced serotonin. Activation of IDO by proinflammatory cytokines leads to the generation of several metabolites of kynurenine including quinolic acid which is an NMDA receptor agonist that can be neurotoxic and contribute to the hippocampal atrophy observed in depression (Cole et al., 2011). Moreover, inhibition of IDO appears to alleviate depressive-like behaviors

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induced by INF-γ or TNFα in animal models (O'Connor et al., 2009a). Observations that patients suffering from severe depression have increased quinolinic acid in microglia in anterior cingulate gyrus support the glutamate hypothesis of depression since these brain regions are known to be responsive to infusion of NMDA antagonists such as ketamine which has rapid antidepressant effects in humans (Duman and Voleti, 2012; Steiner et al., 2011; Salvadore et al., 2010). The purinergic ion channel, P2X7, which controls release of mature IL-1β, is highly expressed on microglia cells (Monif et al., 2010). Interestingly, activation of this receptor down-regulates the expression of glutamate transporters leading to increased levels of glutamate in spinal cord cultures (Morioka et al., 2008). Clinical studies Pro-inflammatory cytokines and depression Numerous studies point to a causal relationship between certain cytokine-based therapies and depression and these have been the subject of prior reviews (Dantzer et al., 2008; Miller et al., 2009; Raison et al., 2006). HIV patients and cancer patients that receive IL-2 or IFNα therapy develop marked cognitive disturbances and neuro-vegetative symptoms of depression (Pavol et al., 1995; Anisman et al., 2007). Other studies have shown that normal volunteers receiving low doses of the bacterial pathogen LPS or live attenuated rubella virus develop depressed mood associated with periods of anxiety and memory deficits (Morag et al., 1999). Common comorbidities with depression include diseases with clear involvement of the immune system including cardiovascular disease, type 2 diabetes (de Groot et al., 2001) and rheumatoid arthritis. For example, individuals suffering a history of myocardial infarction have elevated inflammatory markers (e.g., TNFα and C-reactive protein—CRP) and a correspondingly high incidence of depression (Halaris, 2009; Johnson and Grippo, 2006; Odeh, 1993). A meta-analysis of patients with rheumatoid arthritis showed a 5.9 fold increase in incidence of depression in the more severely affected patients Godha et al., 2010. These three lines of clinical evidence, induction of depression with cytokine therapies, increased incidence of depression in the population affected by autoimmune and chronic diseases involving inflammation, and elevated biomarkers of inflammation (see below), provide the basis for the inflammation hypothesis of depression. While there is good evidence suggesting that inflammation can contribute to the development of depression it is less evident that blocking inflammation will lead to a reduction of depressive symptoms or be efficacious in treatment-resistant depression. Ultimately, the neuroinflammation hypotheses will need to be tested in the clinic. Anti-inflammatory agents such as celecoxib and ω − 3 fatty (eicosapentanoic) acid have been shown to be moderately effective in treating depression in some instances (Muller et al., 2006; Song and Zhao, 2007). Additional trials are ongoing using celecoxib in combination with an SSRI (Akhondzadeh et al., 2009). Evidence is beginning to emerge that direct inhibition of TNFα activity in the periphery by way of neutralizing antibodies or proteins may provide relief of depressive symptoms in patients suffering from chronic inflammation. For example patients treated with etanercept for psoriasis, showed significant improvements in depressive symptoms and fatigue (Tyring et al., 2006). In a more recent study evaluating infliximab in ankylosing spondylitis (Ertenli et al., 2012), similar improvements in clinical depression scores were observed, and in both studies these were uncorrelated with scores reflecting improvements in the primary disease. Both diseases strongly implicate TNFα and IL-1β in the disease pathology, and therefore we can speculate that in some individuals depression is secondary to the chronic state of primary inflammation. It will be interesting to determine if cytokine neutralizing approaches will be effective in treating depression in patients who exhibit elevated inflammatory markers in the absence of comorbidities (although such patients may be hard to find). A recent proof-of-concept study of treatment-resistant, depressed patients showed no general effect of TNFα inhibitor administration on

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mood scores, but revealed a subset of responders with high baseline TNFα (Raison et al., 2012). Thus, direct targeting of key mediators of inflammation may improve depressive symptoms in a subset of patients with high inflammatory biomarkers. As additional results become available it is hoped that new conclusions can be drawn regarding the role for inflammatory cytokines in the symptomatology of major depression. The link between cytokine therapies and depression is further substantiated by alterations in tryptophan metabolism, similar to the preclinical observations discussed above, that also occur in patients receiving immunotherapy for HIV. Thus, in humans, depression triggered by IFNα causes an increase in IDO activity that directs tryptophan metabolism away from 5-HT and toward the production of kynurenine, and ultimately toward production of the neurotoxin quinolinic acid (Capuron et al., 2002). PET and FMRI studies of patients receiving IFNα therapy reveal altered metabolic activity in basal ganglia that may relate to anhedonia, as well as changes in anterior cingulate cortex activity that may subserve reduced information processing (Capuron et al., 2005). Glutamate metabolism is substantially altered by IL-1β and TNFα both because of the production of quinolinic acid, which activates NMDA receptors, and because of a down regulation of the principal glutamate transporter EAAT located on astrocytes (Khairova et al., 2009). Inhibition of EAAT causes “spillover” of glutamate onto both extrasynaptic NMDA and metabotropic glutamate receptors (mGluRs) with a variety of

negative consequences. Numerous studies link the mGluR family to potential treatment for psychiatric conditions both in pre-clinical and clinical settings (for review see Nicoletti et al., 2011). A role for mGluRs in neuroinflammation was initially assigned to pathways associated with sensation of pain (Neugebauer et al., 1994) but more recently relevance is seen in models of psychiatric disorders. Microglia and reactive astrocytes express mGluR subtypes mGluR3, 4 and 5, and this expression is differentially up- or down-regulated upon activation depending upon subtype (Drouin-Ouellet et al., 2011; Berger et al., 2012). These mGluRs have differential effects on microglial activation and the inflammation response (Berger et al., 2012; Byrnes et al., 2009). Interestingly, cinnabarinic acid which is an endogenous metabolite of the kynurenine pathway has been shown to activate mGluR4 providing a link between glutamate signal transduction and neuroinflammation (Fazio et al., 2012). It is worthwhile to note that antidepressant therapies, such as SSRIs, certain tricyclics, and electroconvulsive shock therapy have been shown to reduce inflammatory markers (Dinan, 2009), although this may not be the case for others such as venlafaxin (Peletz et al., 2008). Depressive symptoms induced by IFNα therapy are also responsive to treatment with SSRIs, but in some instances the depressive symptoms are so severe as to require cessation of treatment. These effects are unlikely to result from complications of the illness because they do not occur with such frequency with other treatment strategies.

Fig. 2. Levels of IL-1β (A) and TNFα (B) in human plasma samples from clinically normal (N = 207) and untreated patients diagnosed with MDD (N = 267) or bipolar disorder (type 1 and type 2, N = 166) from Lundbeck-sponsored clinical trials. Plots on left display mean ± standard errors; plots on the right show all data points. The cytokines were quantified using a “high sensitivity” kit for TNFα, IL-1β IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, and IFN-γ human cytokines (Luminex, Millipore). In addition to IL-1β and TNFα, IL-2, IL-4, IL-8, and GM-CSF were significantly elevated in both MDD and bipolar patients relative to normals. ***p b 0.001 vs. normals using ANOVA with Bonferroni post-test.

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The observation that patients with SSRI-resistant depression have significantly higher production of CRP, IL-6 and TNFα than normal controls further suggests a patient stratification approach that may be used in future clinical trials (Yoshimura et al., 2009; for review see Müller et al., 2011). Results of one of the few longitudinal studies published to date suggest that depressed patients reach only a partial normalization of HPA axis function after long-term treatment with SSRIs (Hernández et al., 2008). Biomarkers The view that depression is secondary to immune activation is supported by observations of elevated plasma cytokines including IL-1β, IL-2, IL-6, TNFα and IFNα, especially in patients with severe depression (Anisman et al., 1999; Maes et al., 1999b; Sluzewska, 1999). Recent meta-analyses have confirmed the association of elevated CRP, IL-6 and TNFα with MDD (Dowlati et al., 2010; Howren et al., 2009). Correlations with IL-1β are less consistent (Dowlati et al., 2010), which may be due in part to the very low concentrations of this cytokine in human plasma. In our hands, a highly sensitive detection method is required to accurately measure plasma levels of IL-1β which often are close to the limit of detection (Fig. 2). Higher blood levels of TNFα, IL-1β, IL-6 and CRP have been shown in some cases to correlate with the severity of depression (Maes et al., 1993b; Lanquillon et al., 2000). Furthermore, increased production of cytokines is observed in mitogen-stimulated peripheral blood mononuclear cells (PBMCs), and the magnitude of these effects correlate with the severity of illness. CRP elevations compared to controls have been suggested as an early marker for cognitive symptoms of depression (Gimeno et al., 2009). Other disturbances of immune function, including changes in circulating lymphocyte subsets, reduced lymphocyte response to mitogens and impaired natural killer cytotoxicity are also associated with mood disorders, particularly melancholic depression (Maes et al., 1993a,b, 1999b). At the receptor level, high levels of TNF-receptors (types I and II) have been proposed as markers for an increased vulnerability for depression (Himmerich et al., 2008). Cytokines, as well as SSRI's upregulate the expression of p11 (Svenningsson and Greengard, 2007) which has been found to be increased in MDD patients (Su et al., 2009). Potentially interesting is the observation that opposite effects on p11 have been observed in PTSD patients (see below, Su et al., 2009). Further, IL-18 has been associated with increased risk of developing depression following a stroke (Yang et al., 2010). Both IL-1β and IL-18 are released via a P2X7-dependent mechanism under conditions with high ATP release such as stroke or head trauma (Fig. 1). Among other actions, release of IL-1β inhibits BDNF (Cavadini et al., 2007; Barrientos et al., 2004) and decreases in BDNF have been correlated with disease severity and anxiety co-morbidity (Satomura et al., 2011). At Lundbeck Research we have analyzed changes in transcription of a range of genes in blood samples from clinical trials including more than 200 patients per group using quantitative PCR in a high throughput mode (Antonijevic et al., 2010; Larsen, 2011). Of relevance to neuroinflammation it is interesting to note that IL-1β, IL-6 and P2X7 are among the genes most consistently regulated in patients suffering from mood disorders. P2X7, a key regulator of IL-1β secretion, is particularly interesting because the gene exhibits numerous polymorphisms, some of which exhibit gain of function (Cabrini et al., 2005; Denlinger et al., 2005; Stokes et al., 2010) and show a significant association with depression (Lucae et al., 2006; Soronen et al., 2011). A polymorphism in the gene encoding IL-1β has been associated with failure to achieve remission and reduced brain activity in areas responsive to emotional components of facial recognition (Baune et al., 2010). In our studies, additional alterations in gene expression are reliably seen for MAPK14 (i.e., p38-α) and extracellular signal-regulated kinases 1 (ERK1/2) which are activated by various environmental stresses and pro-inflammatory cytokines. One can

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argue that looking at changes in gene expression in a peripheral tissue, such as whole blood, will have limited relevance to a disease primarily involving the brain, but there are examples of genes, such as BDNF and plasminogen activator inhibitor-1, that show unexpected changes in blood samples that are highly relevant to our understanding of the roots of depression (Sen et al., 2008; Tsai et al., 2008). With a growing appreciation of the role of microglia and classical elements of the innate immune signaling network in the brain, a strong case is made to look for pathological changes that may be mirrored in an accessible peripheral source. The possibility of using combinations of inflammation-related biomarkers for defining patients' segments, or for predicting response to treatment, may eventually be of great benefit to patients. Post-traumatic stress disorder PTSD is classified as a severe anxiety disorder that develops following exposure to physical or psychological trauma. Symptoms of illness include the occurrence of flashbacks associated with the traumatic event, hypervigilance, increased arousal and anger. Research has focused on changes in regulation of the stress response by the HPA axis (for review see Goshen and Yirmiya, 2009), effects on memory function and activation of innate immune responses. Preclinical studies Studies in the past 20 years have demonstrated the effects of both acute and chronic stress on memory functions and the role of inflammatory mediators in synaptic plasticity in animals. Studies involving acute stress in rats showed that changes occur in CNS centers regulating the stress response by the hypothalamus and fear memories by the amygdala. As mentioned previously, a variety of evidence shows that cytokines such as IL-6, TNFα and especially IL-1β are upregulated in specific regions of the brain, such as amygdala, hippocampus and hypothalamus, following either physical or psychological stress to mice or rats (Deak et al., 2005; Koo and Duman, 2008; Pugh et al., 1999; Zhou et al., 1993). There are both peripheral, via activation of the sympathetic nervous system, and central sources of cytokines which may depend upon the nature and duration of the stressor (for review see Raison et al., 2006). The precise cellular sources of stress-induced cytokines such as IL-1β and IL-6 are not known with certainty, however, their effects on brain function relevant for anxiety, fear, and memory are becoming increasingly clear and their receptors are abundantly expressed on neurons of the hypothalamus, hippocampus, especially the dentate gyrus, and more sparsely, in the amygdala (French et al., 1999; Schöbitz et al., 1993; Wong and Licinio, 1994). Possibly relevant for understanding the pathological retention of unpleasant traumatic memories in PTSD are numerous studies of the effects of IL-1β on memory formation and consolidation. Maier and Watkins (1995) were the first to show that blockade of IL-1β signaling modulates memory function using the learned helplessness procedure. Interestingly, low levels of this cytokine appear to be necessary for normal synaptic plasticity since mice lacking the receptor for IL-1β, and rats provided with a central source of IL-1Ra, show impairment of normal memory function (Goshen et al., 2007). Overexpression of IL-1β or icv doses of IL-1β, however, also impairs memory function. This manifests as an attenuation of hippocampal LTP (Kelly et al., 2003) and reduction in performance in spatial memory and fear conditioning (Cunningham and Sanderson, 2008; Moore et al., 2009). A hallmark of PTSD is the inability of patients to modulate their responses to contextual cues, as if a danger signal were present in a safe environment. This abnormal behavior has been modeled in rats using differential contextual odor conditioning (Cohen et al., 2009). In this model the presence of a strong stressor diminishes the ability of the trained animal to respond appropriately to a neutral or rewarding

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context, and instead, the threatening context is remembered. Brain structures involved in processes relevant for PTSD, such as fear conditioning, habituation and extinction, include principally medial prefrontal cortex, amygdala and hippocampus (Liberzon and Sripada (2008). Although much is known about how the HPA axis affects the function of these brain regions at the circuit level, and glucocorticoids clearly regulate inflammation signaling, additional work needs to be done to reveal details of a direct role of IL-1β and other cytokines in the regulation of fear memories. Clinical studies and biomarkers In humans, physical and psychological stress, and trauma in particular, are associated with elevations in plasma IL-6, as well as cortisol and catacholamines, as a result of activation of the HPA and the sympathetic nervous system. Several studies of patients who developed PTSD as a result of accidental or combat-related trauma have shown elevated IL-6 in serum collected 4–9 months after the traumatic event (Maes et al., 1999a; Baker et al., 2001; Gill et al., 2008). This relationship remained significant in one study when accounting for patients with comorbid depression (Maes et al., 1999a). Circulating levels of IL-1β and TNFα have also been reported to be chronically elevated in PTSD patients (Spivak et al., 1997; von Känel et al., 2007), and in one study IL-1β levels were significantly reduced following treatment of symptoms with an SSRI (Tucker et al., 2004). Neither study supported a correlation between IL-1β and cortisol levels which could be explained by previous suggestions of suppressed HPA functioning in PTSD patients. Although glucocorticoid synthesis is suppressed by IL-6 and IL-1b, and these cytokines enhance HPA activity, no consistent correlation between cytokine and glucocorticoid levels has emerged in studies of PTSD patients so far (Apfel et al., 2011). A more recent study using a multiplexing technology reported a wide variety of cytokines involved in the peripheral inflammatory response were found elevated in patients with PTSD or panic disorder (Hoge et al., 2009). It is worthwhile noting that acute psychological stressors, such as public speaking or performing complex tasks in public, also transiently elevate plasma cytokines (Deinzer et al., 2004; von Känel et al., 2006). Since it is thought that the hippocampal–amygdala catecholaminergic structures play an important role in fear reactions, fear conditioning, encoding, and retrieval of traumatic memories as well as sensitization, it is reasonable to hypothesize that norepinephrineinduced secretion of proinflammatory cytokines, such as IL-1β and IL-6, is involved in the pathophysiology of PTSD. The fact that centrally administered IL-1β has been shown to be a powerful stimulus for plasma IL-6 in non-human primates (Xiao et al., 1999) suggests that a susceptibility to developing PTSD may result from a hypersensitivity in the central IL-1β pathway. IL-6 has also been found to be elevated in CSF of patients diagnosed with PTSD subsequent to combat-related stress (Baker et al., 2001). It is likely that the underlying source of elevated cytokines in PTSD is of CNS origin, but this is difficult to prove. One study of children demonstrated a correlation between elevated IL-6 immediately post trauma and development of PTSD symptoms four months later (Pervanidou et al., 2007), suggesting a causal relationship between the IL-6 response and development of PTSD. The S100 family of protein, p11 has also been proposed as a marker to distinguish PTSD from other psychiatric conditions since patients with PTSD had lower levels of p11 mRNA than control subjects, while those with major depression or bipolar disorders had higher p11 levels than the controls (Su et al., 2009). However, this study was performed with a very small number of patients and thus needs replication in larger cohorts to confirm the overall validity of these findings. Few clinical studies support mechanistic hypotheses for how inflammatory signals may underlie PTSD disease or symptomatology. Perhaps the best supported link is between IL-1β and hippocampal volume. There is good evidence from animal models that this cytokine mediates

the stress-induced inhibition of hippocampal neurogenesis, as discussed earlier, and further, that hippocampal volume is decreased by chronic stress and IL-1β (Golub et al., 2011; Hein et al., 2012). Numerous studies have reported reduced hippocampal volumes in patients with PTSD (Bonne et al., 2008; Woon and Hedges, 2011). In one recent study, Apfel et al. (2011) found hippocampal volume correlated with current but not lifetime PTSD symptom severity. It is not known whether hippocampal size represents a risk factor for developing the illness, or if volume reduction is reversible once PTSD symptoms remit. Nevertheless, it is interesting to speculate that hippocampal volume reduction widely associated with PTSD (Bonne et al., 2008) is a biomarker that is mechanistically related to the neurochemical sequelae of IL-1β overproduction. Bipolar disorder Preclinical studies Key features of bipolar disorder, such as vulnerability to episodes of depression and mania and in particular, spontaneous cycling, have been very challenging to capture in animal models (for a recent review see Young et al., 2011). Recent genetic models based on disruption or over-expression of CLOCK, ERK1, GSK3β and P11 genes exhibit some of these features, especially the hyperactivity associated with mania and sleep disturbances that pervade the disorder (Chen et al., 2010). The limited profiling of these and other animal models that capture features of mania, such as increased reactivity and motor activity, so far has revealed disturbances in circadian function, dopaminergic activity, and cortical synchrony, but effects on immune-related functions have not yet been reported. Nevertheless, associations may be drawn based on the mechanism of action of current therapeutics in relation to other disease areas. Using a mouse model of Alzheimer's disease Kitazawa et al. (2011) report that blocking IL-1 receptor activity alleviates cognitive deficits and attenuates tau pathology, in part, through inhibition of GSK3β-mediated tau hyperphosphorylation. Since one of the principle actions of the mood stabilizer lithium is through inhibition of GSK3β, the possibility exists for an anti-inflammatory effect. In fact, lithium and other drugs such as histone deacetylase (HDAC) inhibitors and valproate have been shown to promote the antioxidant response in astrocytes and thereby protect against damage from activated microglia (Correa et al., 2011). It will be important to study the temporal nature of changes in immune function signaling because of the cyclic nature of the disease. One can imagine that bipolar depressive episodes have pathophysiological mechanisms in common with major depression, while manic episodes characterized by hyperexcitability are mechanistically distinct, but this remains to be demonstrated. Clinical studies Expression profiling studies reveal that bipolar and major depressive disorders share common regulatory changes. For example, several investigations including our own have reported increases in inflammatory markers, such as IL-1β, IL-6, CRP and TNFα, in plasma samples and in monocytes from bipolar patients (Fig. 2; Goldstein et al., 2009). More recent studies are beginning to address the episodic nature of the illness by stratifying patients into manic or depressed states. Söderlund et al. (2011) describe a substantial elevation of IL-1β in cerebrospinal fluid from a cohort of 30 patients with bipolar disorder compared to healthy controls. Curiously, IL-1β was highest in the subgroup of patients who experienced a recent manic episode, suggesting that inflammatory tone may vary over time with affective state. Another group has reported significant associations between inflammatory markers in plasma and affective symptoms (Hope et al., 2011). In a study of bipolar-depressed patients, Drexhage et al. (2010) report changes in expression of other pro-inflammatory genes including triggering receptor expressed on myeloid cells-1

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(TREM-1) and its transcription factors. Of the cytokines tested only the monocyte/macrophage cytokines CCL2 and PTX3 were significantly higher in the serum of bipolar depressed patients as compared to healthy controls. Of note, a polymorphism in the gene encoding P2X7, previously discussed in relation to depression, is also associated with a prevalence for bipolar disorder (Barden, et al., 2006). In more recent studies, these polymorphisms have been linked to disease severity (Soronen et al., 2011) as well as to bipolar-specific cognitive symptom domains, such as talkativeness, distractibility and disordered thought (Backlund et al., 2011). Finally, expression of p11 in blood cells has been proposed as a biomarker for bipolar disorders when combined with measurements of regional brain activity by PET imaging (Zhang et al., 2011). Overall, several promising biomarker candidates have been brought forward recently which indicates that a defined, validated biomarker for these diseases may become a reality within the next few years. Future directions — novel treatment opportunities Several approaches can be taken to target mechanisms that regulate neuroinflammation in a potentially efficacious manner. These include targeting cytokines directly or via down or upstream pathways. Dozens of different cytokines regulate immune function, but the number believed to have a role in the CNS is much more limited and includes primarily IL-1β, IL-6, TNFα and IFNα and their cognate receptors. There are no small molecule inhibitors available for these receptors; therefore, therapies are limited to antibodies and other biologics, such as etanercept (TNFα inhibiting protein), anakinra (IL-1Ra) and IL-6 antibodies (in development), that may not efficiently enter the brain. Downstream effectors of cytokine activity, such as p38 MAPK, jun-C kinase and ERK1/2, are drugable targets and p38 MAPK inhibitors are being pursued by the pharmaceutical industry. Alternatively, it is possible to modulate upstream signaling by blocking early stimuli that elicit cytokine release. P2X7 antagonists will abolish IL-1β release via blockade of this important receptor/ channel for ATP (Abbracchio et al., 2009; North, 2002). Although drugs developed for this receptor did not show clinical efficacy for rheumatoid arthritis (Gunosewoyo et al., 2007; Stock et al., 2012), they may be efficacious for other diseases where this pathway is more relevant. Modulation of MC4 or angiotensin II receptors also holds promise as indirect means to dampen neuroinflammation (Benicky et al., 2011; Gonzalez et al., 2009). The question of central vs. peripheral origin of neuroinflammation is an important one, not only for understanding disease etiology, but also for selecting the best therapeutic approach. Recent studies suggest that neutralizing plasma IL-1β or TNFα with intravenous administration of antibodies or trapping proteins reverses many of the behavioral and biochemical perturbations observed in animal models of depression (R. Duman, pers. comm; Jiang et al., 2008). These studies suggest that therapeutics targeting the periphery may be relevant for treating central manifestations of disease. Indeed a strong case can be made, in general, for targeting IL-1β and IL-1 receptor function as a therapeutic strategy (Koo and Duman, 2009). A macro-molecular complex termed the inflammasome regulates release of the active form of IL-1β (Di Virgilio, 2007; Franchi et al., 2009). Point mutations in inflammasome pathway elements cause rare forms of an autoinflammatory syndrome in humans, which may suggest disease-relevant entry points for drug discovery. Caspase-1 inhibitors, such as VX-765, in development for treatment-resistant partial epilepsy, and TLR4 inhibitors such as naloxone (Hutchinson et al., 2008), are examples, but with the more recent discovery of new elements of the inflammasome, such as NALP3 (Di Virgilio, 2007; Franchi et al., 2009), it may be possible to identify better targets with improved CNS selectivity. It could be desirable to selectively target CNS-specific components of the innate immune system, such as the recently described neuron-specific isoform of the IL-1 receptor (Huang et al., 2011).

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A prerequisite for successful introduction of a novel antidepressant, which mediates its effects through a neuroinflammation mechanism, would be the ability to identify patient populations that are not adequately treated with standard care and to predict which of these patients would benefit from the novel drug. A distinct opportunity within neuroinflammation biology is the abundance of relevant biomarkers in blood cells. Thus, it is very feasible to measure both transcriptional as well as protein (e.g., cytokine) levels from whole blood and plasma, respectively. Many clinical trials are now routinely collecting whole blood for expression and protein profiling, and some are employing flow cytometry as a means of phenotyping specific populations of circulating immune cells (Denlinger et al., 2005). It is also possible to genotype and functionally characterize cryopreserved PBMCs obtained from a variety of patient populations to assess functional differences between normals and patients, as well as to assess drug efficacy within specific pathways during patient treatments. Although cost is a factor, use of cryopreserved PBMCs (from patients) permits sophisticated functional analyses to be performed which can complement more traditional expression profiling. Biomarker and functional results can be assembled with clinical assessments to shed light on which inflammatory pathways are affected in different patient segments.

Conclusions Abundant evidence points to an association of elevated inflammatory markers in mood disorders. Both peripheral and central mechanisms contribute to a chronic inflammatory state. The regulation of cytokines and other immune mediators of inflammation and their impact on brain function are beginning to be understood at molecular and systems levels. Further study of peripheral biomarkers, readily accessible from patient plasma and blood samples, will reveal pathophysiologies in common with the CNS, as well as stratification approaches that may improve treatment outcome. New therapies directed at specific control points of inflammation may prove effective for treating relevant subpopulations of patients with mood disorders.

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