Prostaglandins, Leukotrienes and Essential Fatty Acids

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Polyunsaturated fatty acids, neuroinflammation and well being Sophie Laye´ n Psychoneuroimmunology, Nutrition and Genetic (PsyNuGen), UMR INRA 1286, CNRS 5226, University Bordeaux 2, 146 rue Le´o Saignat, 33077 Bordeaux, France

abstract The innate immune system of the brain is principally composed of microglial cells and astrocytes, which, once activated, protect neurons against insults (infectious agents, lesions, etc.). Activated glial cells produce inflammatory cytokines that act specifically through receptors expressed by the brain. The functional consequences of brain cytokine action (also called neuroinflammation) are alterations in cognition, mood and behaviour, a hallmark of altered well-being. In addition, proinflammatory cytokines play a key role in depression and neurodegenerative diseases linked to aging. Polyunsaturated fatty acids (PUFA) are essential nutrients and essential components of neuronal and glial cell membranes. PUFA from the diet regulate both prostaglandin and proinflammatory cytokine production. n-3 fatty acids are anti-inflammatory while n-6 fatty acids are precursors of prostaglandins. Inappropriate amounts of dietary n-6 and n-3 fatty acids could lead to neuroinflammation because of their abundance in the brain and reduced well-being. Depending on which PUFA are present in the diet, neuroinflammation will, therefore, be kept at a minimum or exacerbated. This could explain the protective role of n-3 fatty acids in neurodegenerative diseases linked to aging. & 2010 Elsevier Ltd. All rights reserved.

1. Introduction Inflammation is an active defence reaction against diverse insults that aims at neutralizing noxious agents. Although inflammation serves as a protective function in controlling infection and promoting tissue repair, it can also cause tissue damage. Inflammatory mediators include complement, adhesion molecules, products of cyclooxygenase enzymes (eicosanoids), and cytokines. Cytokines are peptides that are generally associated with inflammation, immune activation, and cell differentiation or death. They include interleukins (IL), interferons (IFN), tumour necrosis factors (TNF), chemokines and growth factors. Although most of them have little or no function in healthy tissues, they are rapidly induced locally in response to tissue injury, infection or inflammation. Inflammatory mediators including cytokines are not only expressed at the site of injury but also in distant organs, including the brain where they coordinate the central component of the acute phase reaction. This brain-mediated response involves in particular profound metabolic alterations, in the form of an increased set-point for thermoregulation resulting in fever, and drastic behavioural changes commonly labelled as sickness behaviour (anorexia, decreased locomotor activity; withdrawal from social contacts, etc). Brain expression of cytokines also plays a key role in the

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pathophysiology of immune (e.g., multiple sclerosis) and nonimmune neurological disorders (e.g., brain injury, stroke, Alzheimer’s disease). Study of the expression and action of proinflammatory cytokines in the brain is a rapidly growing area of experimental and clinical research. Because of the number of cytokines and the diversity of their actions, this review will focus primarily on the cytokine that has been studied the most extensively in the brain, interleukin-1 (IL-1). In the brain, inflammatory mediators are mainly produced by endothelial cells and glial cells, including astrocytes, and microglia [1]. The expression of proinflammatory cytokines in the brain is increased in response to various conditions, such as infection (bacteria, viruses, y), lesions, trauma, and oxidative stress. Neuroinflammation, the inflammatory response in the brain, has many cellular and biochemical features that make it different from the peripheral inflammatory response. Functional consequences of neuroinflammation include alterations in cognition, affect and behaviour, and they usually take place in the absence of neurotoxicity [2]. The behavioural repertoire of humans and animals is well known to change dramatically during the course of an infection. Ill individuals have little motivation to eat, are listless, complain of fatigue and malaise, loose interest in social activities and have significant changes in sleep patterns. They feel sick and in pain, display an inability to experience pleasure, and experience difficulties in attention, concentration and memory [3]. These alterations are responsible for impaired quality of life and well being. All these functional alterations can be reproduced in naı¨ve individuals by

0952-3278/$ - see front matter & 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2010.02.006

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peripheral or central injection of proinflammatory cytokines [4]. When neuroinflammation is exacerbated or prolonged, it can lead to neuronal cell death and neurodegeneration as a consequence of the deprivation of neurons of their growth factors or the overproduction of reactive oxygen species [1,5]. As far as neurodegeneration is concerned, it is unclear if this condition is propagated through inflammation, or whether in contrast, the inflammatory response reflects an attempt to protect against further cellular injury. There are multiple aspects of neuroinflammation, all occurring simultaneously. Following exposure to noxious stimuli, components of neuroinflammation include activation of microglial release of cytokines, and induction of tissue repair enzymes, that together limit cellular damage and promote repair. At the behavioural level, cytokine-induced sickness behaviour is nothing else than the outward manifestation of a central motivational state that helps the body to fight infection and promote recovery [2]. The extent of neuroinflammation is normally regulated by a variety of opposing processes involving anti-inflammatory cytokines such as interleukin (IL)-10, growth factors in the form of for instance insulin-like growth factor 1 (IGF-1), hormones such as glucocorticoids, neuropeptides such as vasopressin and a-melanotropin and endocannabinoid through their action on CB2 receptors [6–9]. Dietary nutrients, in the form of antioxidants and polyunsaturated fatty acids (PUFA) are also able to regulate neuroinflammation. PUFA are incorporated into cell membranes. The composition of cell membranes determines the type of inflammatory mediators that will be produced during the inflammatory response. It is generally considered that humans evolved on a diet with a ratio of n-6 to n-3 PUFA equal approximately to 1, whereas today this ratio is closer to 10–20, indicating that Western diet is typically deficient in n-3 PUFA [10–12]. The relative excess of n-6 fatty acids promotes the formation of arachidonic acid (ARA), the fatty acid precursor of PGs and other eicosanoids involved in inflammation, and which are important in chronic inflammatory disease. In contrast, eicosanoids derived from eicosapentaenoic acid (EPA) are less physiologically potent than the mediators synthesized from ARA [13]. Moreover, n-3 fatty acids, such as docosahexaenoic acid (DHA) and its derivatives display antiinflammatory effects and inhibit the production of proinflammatory cytokines independent of the production of eicosanoids. Since feeding animals or human subjects with regimens enriched with DHA and EPA results in a decrease of the amount of ARA in glial cell membranes, there will be less substrate available for synthesis of eicosanoids from ARA [14–16]. Because n-3 PUFA are anti-inflammatory and are preferentially incorporated in the brain, inappropriate amounts of dietary n-6 and n-3 fatty acids could promote neuroinflammation. Depending on the relative amounts of n-6 and n-3 PUFA present in the diet, neuroinflammation will, therefore be kept at a minimum or exacerbated. The aim of the present paper is to review the mechanisms of neuroinflammation, its functional consequences and its modulation by PUFA.

2. Neuroinflammation For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens [17]. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The hallmark of brain inflammation is the activation of glia, particularly microglia [18]. Microglial cells are sensor cells in the central nervous system that respond to

injury and brain disease [19]. These cells are able to scavenge invading microorganisms and dead cells, and also to act as immune or immunoeffector cells [20]. In physiologic conditions, the brain contains resting microglia, perivascular macrophages, and pericytes, as well as a few patrolling lymphocytes. The origin of pericytes, perivascular macrophages, and microglia found in the adult brain is probably represented by systemic monocytes that infiltrate the CNS during embryogenesis [19,21]. In pathological conditions, all these cells become activated and are strongly involved in the local inflammatory response [22]. In particular, resting microglial cells become activated and change the phenotype to amoeboid microglia capable of phagocytosis. This is accompanied by the production of proinflammatory cytokines, in particular IL-1, nitric oxide, superoxide anions and eicosanoids [20,23,24]. Cell wall components of the Gram-negative or Gram-positive bacteria (lipopolysaccharide (LPS) and peptidoglycan, respectively) function as pathogen associated molecular patterns (PAMPs) that are recognised by specific membrane receptors on innate immune cells [25]. LPS and peptidoglycan bind to toll-like receptors (TLR) [25]. While TLR2 recognizes PAMPs produced by Gram-positive bacterial cell wall components, TLR4 is critical for the recognition of LPS. Flagellin, the principal element of bacterial flagella, is recognised by TLR5, and TLR9 is required for the inflammatory response triggered by bacterial DNA. TLR3 induces an innate immune response to double-stranded RNA (dsRNA) viruses. Microglia is the main cellular component of the innate immune system in the brain. The peripheral administration of LPS activates systemic innate immune cells, which results in the production and extracellular release of proinflammatory cytokines [26–29]. Once present in the bloodstream, these cytokines are believed to mediate most of the effects of systemically injected LPS, although circulating levels of cytokines are not necessarily detectable prior to the occurrence of the early physiological responses that are induced by the endotoxin [30]. The best example is fever that takes place within minutes in response to a systemic injection of LPS, even though cytokines are not yet detectable in the bloodstream [30]. Because of this temporal constraint, LPS has been proposed to be a direct ligand in the brain. In accordance with this hypothesis, cytokine gene expression in response to a peripheral LPS challenge is first detected in the circumventricular organs (CVO) that are devoid of a blood–brain barrier (BBB), leptomeninges and choroid plexus (ChP) [26,29,31]. The demonstration that CD14 and TLR4 are constitutively expressed in the CVO and in parenchymal microglia reinforces this idea [18,27,32]. Circulating LPS also causes a rapid increase in CD14 in these brain regions, and a delayed response takes place in cells located at the boundaries of the CVO and in microglia across the brain parenchyma [33]. A similar expression pattern was recently found for the gene that encodes TLR2 in the brains of mice after a single systemic injection of LPS. The signal was first detected in regions devoid of BBB and a second wave was detected in parenchymal microglial cells [33]. Interestingly, TLRs and IL-1 receptors share a cytoplasmic motif, the Toll/IL-1 receptor (TIR) domain, which is required for initiating intracellular signalling [34,35]. The TIR family of receptors uses very similar signalling mechanisms to activate downstream effector mechanisms (Fig. 1). While some components of the downstream signalling machinery like the adapter TNF receptor associated factor 6 (TRAF6) are shared by other receptors of proinflammatory cytokines, one signalling module is exclusively employed by the TIR family. This consists of MyD88, interleukin-1 receptor associated kinase (IRAK) family members and Tollip. TRAF6 directly facilitates full activation of the nuclear factor kappa B (NFkB) pathway and the mitogenactivated protein kinase (MAPK) signalling cascades. In

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Fig. 1. Signalling pathways activated by the IL-1 family and receptor complex. The IL-1 family is composed of two agonists, IL-1a and IL-1s and a natural antagonist, IL-1ra. IL-1 agonists bind to the type 1 IL-1 receptor (IL-1R1) and then interact with IL-1 receptor accessory protein (IL-1RacP). They form a functional heterodimeric complex that activates downstream signalling pathways involving NFkappaB (NFkB) and the mitogen-activated protein kinase (MAPK) family. This activation requires the formation of a complex between IRAK (IL-1 receptor associated kinase), MyD88 and Tollip. This complex activates TNF receptor associated factor 6 (TRAF6) leading to the phosphorylation and degradation of the NFkB inhibitor, IkB and the activation of the MAPK family.

unstimulated cells, NFkB family proteins exist as heterodimers or homodimers that are sequestered in the cytoplasm by virtue of their association with a member of the inhibitor kB (IkB) family of inhibitory proteins (Fig. 1). These interactions mask the nuclear localization sequence of NFkB and interfere with sequences important for DNA binding. The destruction of IkB unmasks the nuclear localization signal of NFkB, leading to its nuclear translocation and binding to the promoters of target genes. The detection of IkB induction reveals the extent and cellular location of brain-derived immune molecules in response to peripheral immune challenges. IkBa mRNA is induced in brain after peripheral LPS injection, beginning in cells lining the blood side of the blood–brain barrier and progressing to cells inside the brain parenchyma [36,37]. The same results were obtained after a peripheral injection of IL-1 and TNFa, but not IL-6. This spatiotemporal pattern indicates that under the effect of LPS, cells of the BBB synthesize immune signal molecules to activate cells inside the central nervous system. The cerebrospinal fluid appears to be a conduit for these signal molecules. As LPS induces the expression of bioactive IL-1 in microglial cells, it is not clear whether the induction of IkB expression in the brain is due to a direct LPS effect on brain cells or to LPS-induced IL-1 produced in the brain [37,38]. A recent study analysed NFkB translocation and IkB expression in the brain and pituitary of rodents treated with IL-1 [39,40]. In this study, the expression of IkB mRNA did not strictly parallel NFkB nuclear translocation. This important finding indicates that peripheral IL-1 can reach the brain across the CVO that lack a BBB and endothelial cells all over the brain and interact with its receptors to induce NFkB translocation.

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IL-1 is bioactive in the brain because there are IL-1 receptors in the brain. Ligands of the IL-1 receptors (two agonists, IL-1a and IL-1R and the natural antagonist, IL-1ra) bind to a transmembrane receptor and to soluble forms of the receptor, which are characterized by extracellular immunoglobulin (Ig) like domains [41]. The prototypes of this family are the IL-1 R type 1 and an accessory protein that functions as a co-receptor molecule, the IL-1RAcP. The receptor chains contain the ligand binding site, whereas the coreceptor IL-1RAcP is unable to bind to the cytokine alone. Indeed, deletion of IL-1R1 or IL-1RAcP, administration of antibodies to IL-1R1 or inhibition of specific MAPK or NFkB abolishes most actions of IL-1 in vivo and in vitro. The type 2 IL-1 receptor (IL-1R2) is a negative regulator of the IL-1 system and functions as a decoy receptor [42].Very recently, new members of the IL-1 family, named IL-1F5–10 were discovered [41]. IL-1F6–F9 have proinflammatory, while IL-1F5 has anti-inflammatory, properties. In addition, the orphan receptors IL-1 R-related protein 2 (IL-1Rrp2), T1/ST2, three immunoglobulin domaincontaining IL-1 receptor-related, IL-1 receptor accessory protein like and single Ig IL-1 receptor-related molecule (SIGIRR), also called TIR8 were demonstrated to belong to the IL-1 R family. IL-1R1 mRNA is diffusely spread across the rodent brain with the highest level of binding in the granular layer of the dentate gyrus, the granule cell layer of the cerebellum, the hypothalamus and the pyramidal cell layer of the hippocampus [43–45]. IL-1R1 is expressed in cells of the choroid plexus and endothelial cells of brain capillaries. Neuronal expression appears mostly in the hippocampus [46]. IL-1RacP mRNA is highly expressed throughout the rat brain [47,48]. However, the presence of the IL-1RAcP in brain areas that lack type 1 IL-1 receptors indicates additional functions for this protein that are still obscure. Very recently, an isoform of the IL-1RAcP (termed AcPb) has been discovered to be exclusively expressed in the brain [49]. In addition, IL-33 the IL-1 like ligand for ST2 is, highly expressed in brain astrocytes [50]. Interestingly, no NFkB activation is observed in the brain of IL1R1 and IL-1RAcP knock-out mice treated with IL-1 [39]. The same effect is observed in mixed glial cells in vitro indicating that IL-1R1 is essential for IL-1beta signalling in the brain [51]. The MAPK p38, c-Jun N-terminal kinase (JNK) and the extracellular signal-regulated protein kinase (ERK1/2) are also activated in glial cells from wildtype mice but not from IL-1R1 knock-out mice. Selective inhibition of p38 or ERK1/2 MAPKs significantly reduced IL-1-induced IL-6 release. Whether this pathway is involved in IL-1 signalling in the brain is still unknown. This is very important since brain-produced IL-1 is a key regulator of the synthesis of other proinflammatory cytokines such as IL-6 and TNFa. Concerning the isoforms of IL-1 (IL-1 F), IL-1F5 antagonizes the inflammatory effects of IL-1 and LPS in the brain [52].

3. Consequence to neuroinflammation: from sickness behaviour to depression Proinflammatory cytokines act in the brain to induce non-specific symptoms of infection, including fever and profound psychological and behavioural changes termed ’’sickness behaviour’’ [4]. Sick individuals experience weakness, malaise, cognitive alterations and listlessness, hypersomnia, depressed activity and loss of interest in social activities [2,53]. Although these symptoms are usually regarded as the result of the debilitation process that occurs during infection, they are actually part of a natural homeostatic reaction the body uses to fight infection [53]. These changes in behaviour have been shown to be the expression of a motivational state that resets the organism’s priorities to promote resistance to pathogens and recovery from

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infection. By preventing the occurrence of those activities that are metabolically expensive (e.g., foraging), and favouring expression of those that decrease heat loss (e.g., rest) and increase heat production (e.g., shivering), sickness behaviour positively contributes to recovery following infection [2]. Sickness behaviour is initiated by cytokines that are induced by infectious agents in the periphery and relayed by centrally produced cytokines [54,55]. Such a role of centrally produced cytokines in sickness behaviour was first provided by comparison of dose-response curves in vivo. In general, centrally injected cytokines induce dramatic behavioural effects at doses that are 100–1000 times less than those needed when they are injected peripherally [56]. Moreover, the behavioural effects of peripherally injected IL-1 were strongly attenuated by central administration of the specific antagonist of IL-1 receptors, IL-1ra, at a dose that was able to inhibit the effects of centrally injected IL-1. The use of neutralizing antibodies directed against specific IL-1 R subtypes strengthened these data. A monoclonal neutralizing antibody specific to IL-1R1 injected into the lateral ventricle of the brain fully abrogated the behavioural effects of centrally and peripherally injected IL-1 [57]. In contrast, the blockade of brain IL-1R2 potentiated the IL-1 effect on food intake but not on body temperature, indicating that some IL-1 actions in the brain are specifically regulated by this receptor [58]. The use of knock-out mice for IL-1R1 and IL-1RAcP reinforce the idea of a specific role of these receptors in mediating IL-1 effect on sickness behaviour [59–61]. However, while the cytototoxic effect of IL-1 in traumatic brain injury was blocked by centrally injected IL-1ra, no blockade was observed in IL-1R1 knock-out mice [62]. Furthermore, central injection of IL-1 exacerbated ischemic brain damage but had no effect on food intake in IL-1R1 knock-out mice. These intriguing data indicate that IL-1 effects in the ischemic brain are independent of IL-1R1. In other words, IL-1R1 would mediate the behavioural but not the cytotoxic effects of IL-1. LPS-induced sickness behaviour has been assessed in a strain of mice (C3H/HeJ) that is hyporesponsive to LPS. These mice have a mutation in TLR4, and it is this deficiency that leads to endotoxin hyporesponsiveness [63]. The hyporesponsive C3H/HeJ mice are completely resistant to the sickness-inducing effects of LPS when injected intracerebroventricularly, but they remain fully responsive to central injections of IL-1 [64,65]. These experiments show that CNS cells derived from C3H/HeJ endotoxin hyporesponders, such as microglia, share with peripheral macrophages the inability to respond to LPS and to synthesize proinflammatory cytokines, therefore impeding development of sickness behaviour. From a practical perspective, these data show that the C3H/HeJ mouse strain is an excellent model that can be used to avoid any potential confounding effects of endotoxin contamination in preparations of recombinant cytokines injected in the CNS. Like at the periphery, the lack of a cytokine in the brain cytokine network can result in compensation by other cytokines that are still present in the network. For instance, peripheral or central administration of LPS still induced sickness behaviour in IL-1R1 knock-out and IL-1RacP knock-out mice that did not respond any longer to IL-1 [55,59–61]. The sensitivity of IL-1R1 knock-out mice to LPS was due to TNF-a replacing IL-1 since central administration of an antagonist of TNF-a blocked LPS action in IL-1R1 knock-out mice but not in wildtype mice [59]. In contrast, the inhibition of proinflammatory cytokine signalling pathways is associated with the improvement in neuroinflammatory processes suggesting that they are not compensated. Indeed, the inhibition of astroglial NFkB by the use of transgenic mice overexpressing a dominant negative form of the IkB superrepressor was associated with reduced neuroinflammation and ischemic damage in the retina [66].

Evidence in favour of a role of cytokines in mediating mood disorders and cognitive disturbances that develop in patients receiving cytokine immunotherapy is growing fast [67]. The same mechanisms appear to be at work for the wide variety of nonspecific sickness symptoms that develop in patients suffering from somatic diseases with an inflammatory component, including coronary heart disease, rheumatoid arthritis, asthma, cancer, stroke, and various neuropathologies [68–71]. Many patients complain of pain, fatigue, anorexia, sleep disturbances, and cognitive and mood disorders. These non-specific neurovegetative and psychiatric symptoms are not necessarily the result of a chain of events linked to each other with more or less a direct cause (e.g., pain induces sleep disorders that impact on cognition and induce fatigue and lassitude, culminating in anorexia) [68]. They could actually just represent another facet of the inflammatory process. These non-specific symptoms are a major source of suffering for the patient, and often more so than the diseased organ itself. Physicians, whatever their skills, are not always wellequipped to deal with these important non-specific symptoms that drastically affect the quality of life of sick patients. The challenge is not only to bring these symptoms to the forefront of the clinician’s attention, but also to be able to treat them adequately (e.g., by molecules that target cytokine production and action in the central nervous system).

4. Neuroinflammation in the aging brain Microglial cell activation contributes to the onset and exacerbation of inflammation and neuronal degeneration in many brain diseases [72,73]. Nonetheless, microglial cells also act in a neuroprotective manner by eliminating excess excitotoxins in the extracellular space [72,73]. Moreover, there is accumulating evidence that microglia produce neurotrophic and/or neuroprotective molecules; in particular, it has been proposed that they promote neuronal survival in cases of brain injury. CNS inflammation occurs in myelin degenerative disorders such as multiple sclerosis (MS) and in neurodegenerative disorders such as Alzheimer’s disease, HIV encephalopathy, ischemia, and traumatic brain injury [74–78]. A general consequence of brain inflammation is reactive gliosis typified by astrocyte hypertrophy and proliferation of astrocytes and microglia [79,80]. Changes in gap junction intercellular communication as reflected by alterations in dye coupling and connexin expression have been associated with numerous CNS inflammatory diseases, which may have dramatic implications on the survival of neuronal and glial populations in the context of neuroinflammation [81,82]. IL-1 exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. In response to local brain injury or insult, like acute head trauma, IL-1 is overexpressed by microglia [1,83,84]. Such acute overexpression of IL-1 has been implicated in the pathogenesis of some forms of acute brain injury. Moreover, patients with multiple sclerosis have elevated levels of IL-1 in the cerebrospinal fluid when their disease is active [85]. Brain microglia may chronically overexpress IL-1 under repeated or persistent injurious stimuli, or chronic neurological conditions (Down’s syndrome, HIV, epilepsy, y). Chronic overexpression of IL-1 is also observed in normal aging brain and in Alzheimer’s disease [86,87,88]. Recent microarray studies, assessing gene expression of Alzheimer-related cytokines, show selective overexpression of IL-1 in Alzheimer’s disease. This increase is coupled with an increase in the expression of IL-1R1 and increased activity of IL-1 receptor-associated MAPK [89,90]. There are genetic associations between IL-1 family gene polymorphisms and

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Alzheimer’s disease, chronic epilepsy and Parkinson’s disease [91–94]. IL-1 overexpression has been implicated in both the initiation and progression of neuropathological changes [83]. Overexpression of IL-1 in Alzheimer brain is linked to an increase in microglia activity that is frequently associated to amyloid plaques [86,95]. This specific distribution suggests a role for IL-1 in the initiation and progression of neuritic and neuronal injury in Alzheimer’s disease, because of its appearance in early plaque formation and its absence in plaques that are devoid of injured neuritic elements. Brains from Tg2576 mice (a model for Alzheimer disease) show significant increases in IL-1 expression compared to controls. Moreover, aged Tg2576 mice mounted an exacerbated cytokine response to LPS that could have amplified the degenerative processes. IL-1 administration depressed food intake more in aged mice than in younger adults [96]. Attenuation of the fever response in old age could be due to the lack of entry of peripheral IL-1 in the brain and not to a lack of brain IL-1 R functionality [97,98]. Age-induced IL-1 overproduction in the brain, and more particularly in the hippocampus, is associated with a decrease in synaptic plasticity measured by long term potentiation (LTP) in the dentate gyrus, that could explain cognitive impairment observed in the elderly [90,99,100]. Receptors for IL-1 are distributed with a high density in the hippocampus, where IL-1 exerts inhibitory effects on release of calcium [101]. There is also evidence for a role of endogenous brain IL-1 in the normal physiological regulation of hippocampal plasticity and learning processes [102,103]. Low levels of IL-1 are essential for memory and plasticity, whereas higher levels of IL-1, as those achieved during aging and neurodegeneration, can be detrimental [102,103].

5. Polyunsaturated fatty acid and neuroinflammation The PUFA linoleic and its n-6 derivative arachidonic acid, and

a-linolenic acid and its n-3 derivatives, EPA and DHA, play key roles in both energy production and cell structure and are indispensable for brain development. ARA and DHA are found in large concentrations in brain lipids. Nearly 6% of the dry weight of the brain is n-3 PUFA [104]. PUFA are incorporated into phospholipids and are key components of the brain cell membranes. They provide fluidity and the proper environment for active integral protein functions. Moreover, phospholipids have a role in cellular function because they are a reservoir of signalling messengers for neurotransmitters or growth factors. There are some data on PUFA contents on neurons and astrocytes, but nothing is known concerning microglial cells. DHA and ARA have beneficial effects when available in moderation. As already mentioned, human beings originally consumed a diet rich in n-3 PUFA and low in saturated fatty acids because wild and free range food animals have much higher content of n-3 fatty acid than do the present day commercial livestock. PUFA were believed to occur in the diet as a ratio 1:1 of n-6 to n-3. Nowadays the ratio is around 10 to 30:1. Excess of n-6 precursors promotes the formation of ARA. Although some ARA is essential, the current high ratio of n-6 to n-3 PUFA may be involved in the increase in chronic inflammatory diseases [13]. A high intake of n-3 PUFA such as DHA or eicosapentaenoic acid (EPA) may have anti-inflammatory effects in patients with neuroinflammation. Conversely, high dietary intake of n-6 PUFA may contribute to the development of the neuroinflammation. ARA is the principal substrate for COX [105]. Additional substrates include cannabinoids and lipoamino acids that can also be oxidized to produce PG precursors for which the pathophysiological role is poorly known [106,107]. PGs have the ability to play

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either a protective or an injurious role, depending on context and quantity produced. Therefore, the membrane levels of their precursor, ARA, are important. EPA contained in membrane phospholipids competes with ARA as a substrate for COX and lipoxygenase (LOX) [108]. The consequences of such a competition are a decrease in the production of inflammatory metabolites such as PGE2, leukotriene A4 (LTA4) and thromboxane A2 (TXA2) and an increase in the synthesis of less inflammatory eicosanoids or even anti-inflammatory ones [109,110]. This has been demonstrated in many cells throughout the body, including glial cells [111]. A 6-day LPS infusion in the brain increased phospholipase A2 activity and brain concentrations of linoleic acid and ARA, and of PGE2 and PGD2 [16]. The occurrence of alteration in n-6 PUFA metabolism in the brain in response to LPS emphasizes again the link between brain PUFA composition and neuroinflammation. Interestingly, mice exposed throughout the life to a diet devoid of n-3 PUFA did not mount sickness behaviour in response to LPS, while IL-6 was overexpressed both at the periphery and in the hippocampus [112]. However, STAT3 and STAT1 activation, a hallmark of the IL-6 signalling pathway, was poorly induced in the hippocampus of LPS-treated mice, suggesting that dietary deficiency in n-3 PUFA dysregulates neuroinflammatory events and the behavioural effect. Numerous studies have revealed that n-3 PUFA inhibit the in vitro production of pro-inflammatory cytokines by macrophages, and their in vivo synthesis in healthy adults and those with autoimmune diseases. However, little is known concerning microglial cells that produce proinflammatory cytokines in the brain. Recently, DHA has been shown to be highly antiinflammatory by targeting LPS receptor surface location, therefore, reducing LPS-induced NFkB activation and proinflammatory cytokines production in microglia [113]. Such an effect could be mediated by the DHA-derived neuroprotectin D1 (NPD1), which regulates Ab peptide-induced proinflammatory cytokine expression in microglia [114–116]. Interestingly, in the brain and in microglia, DHA is also converted to potent anti-inflammatory products called 17-resolvins by aspirin-acetylated COX-2 [117]. Resolvins block production of cytokines by microglial cells. Moreover, they protect from ischemia by blocking NFkB activation and proinflammatory cytokine production [118]. A short duration n-3 PUFA supplementation attenuated the fever responses induced in rats by both i.p. and i.c.v. IL-1 without altering the thermogenic capacity of the organism [119,120]. However, the group of Kluger reported that fever, lethargy and anorexia were differentially regulated by a fish-oil diet depending on the inflammatory stimulus used [121]. Turpentine is a model of local inflammation that induces a robust acute phase response consisting of fever, anorexia, cachexia, and acute phase protein production. Fish oil diet exacerbated LPS-induced lethargia and decreased temperature whereas it blocked turpentine-induced fever, lethargia and anorexia [121]. These changes were associated with a decrease in circulating LPS-induced PGE2 and an increase in LPS-induced TNF-a. Because TNF-a production is partially regulated by PGE2, fish oil could up regulate TNF-a production by decreasing PGE2 production [122]. In mice, the early hypothermic phase of fever to a high dose of LPS was exacerbated by TNF-a treatment, whereas administration of the soluble TNF receptor, a blocker of TNF-a activity, attenuated hypothermia [123,124]. It is questionable, therefore, whether ingesting high amounts of n-3 PUFA during inflammatory events is beneficial. Further studies on the role of PUFA in neuroinflammation are clearly needed. Elderly people who eat fish or seafood, that are highly enriched in n-3 PUFA, at least once a week are at lower risk of developing dementia, including Alzheimer’s disease [125–127]. Because aging is associated with a decrease in membrane PUFA, including

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ARA, and an increase in brain IL-1 production, Lynch proposed that the age-increased IL-1 production is linked to an agedecreased membrane ARA [90,100]. Therefore, IL-1, by impacting on membrane composition, would contribute to age-related impairments in neuronal function. IL-1 increased lipid peroxidation in hippocampal tissue from young but not old rats, and this effect was associated with decreased LTP [90,100]. A short time supplementation in ARA, in combination with another long chain n-6 PUFA, g-linolenic acid (GLA), reversed the age-related impairment in LTP [128]. EPA had a similar effect and, in this case, there was evidence that this effect was a consequence of its ability to block the effects of IL-1, providing support for the hypothesis that EPA acts as an anti-inflammatory agent [129,130]. The anti-inflammatory effect of EPA could be due to the blockade of the IL-1 signalling pathway MAPK, and more particularly p38, in the brain (130). Interestingly, LPS-induced p38 activation in the hippocampus is accompanied by an increased activation of NFkB of which the pharmacological inhibition partially suppresses the inhibitory effects of LPS and IL-1 on LTP and sickness behaviour [39,131,132]. In addition, n-3 PUFA might protect the brain from the deleterious effects of IL-1. Irradiation induced increases in IL-1, IL-1R1 and IL-1RAcP concentrations in the hippocampus. These changes were coupled with an increased activation of JNK and apoptotic cell death. Rats that had been fed a diet rich in EPA did not display any of these events. The anti-inflammatory cytokine IL-10 could explain the anti-inflammatory and neuroprotective effects of EPA in the brain, because EPA increased IL-10 levels and IL-10 blocks the IL-1 effect [133,134]. An EPAsupplemented diet, but not ARA, significantly attenuated centrally injected IL-1-induced anxiety behaviour. Such an effect was also observed in the brain of olfactory bulbectomized mice [135]. This was accompanied by a decrease in IL-1-induced PGE2 and an increase in IL-10 or IL-4 [136–138].

6. Conclusion There is growing evidence that the expression and action of proinflammatory cytokines in the brain are responsible not only for the development and maintenance of sickness behaviour during the host response to infection, but also for the occurrence of non-specific symptoms of sickness during chronic inflammatory disorders. In addition, neuroinflammation can have detrimental consequences on neuronal viability especially when maintained over long periods of time and transiently amplified by peripheral infectious episodes. All of this points to the interest of finding new ways of controlling inflammation in the brain. Because of their abundance in the brain and their modulatory role on inflammation and cell functions, PUFA have certainly a role to play. However, this role still needs to be better characterized by multidisciplinary studies aiming at assessing the effects of these molecules at different levels of functioning, from the molecular to the organism level.

Acknowledgements Supported by INRA and Conseil ge´ne´ral d’Aquitaine.

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