Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA)
Polyunsaturated fatty acids, neuroinflammation and well being
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 pathophysiology of immune (e.g., multiple sclerosis) and non-immune 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, …), 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 naïve individuals by 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 α-melanotropin and endocannabinoid through their action on CB2 receptors [6], [7], [8], [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], [11], [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 anti-inflammatory 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], [15], [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.
Section snippets
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
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
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
Polyunsaturated fatty acid and neuroinflammation
The PUFA linoleic and its n-6 derivative arachidonic acid, and α-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
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
Acknowledgements
Supported by INRA and Conseil général d’Aquitaine.
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