ARTICLE
ocl.2011.0412
Auteur(s) : Sophie Layé1,2 sophie.laye@bordeaux.inra.fr,
Jean-Christophe Delpech1,2, Véronique De Smedt-Peyrusse1,2, Corinne Joffre1,2, Thomas Larrieu1,2, Charlotte Madore1,2, Agnès Nadjar1,2, Lucile Capuron1,2
1 Nutrition et neurobiologie intégrée,
Inra UMR 1286,
Bâtiment UFR Pharmacie,
2̊ tranche,
2̊ étage,
Case courrier 34,
Université Victor Ségalen,
146 rue Léo Saignat,
33076 Bordeaux,
France
2 University of Bordeaux,
Bordeaux,
33077, France
The central nervous system (CNS) has long been considered a
privileged organ from the point of view of immunity, as the blood
brain barrier (BBB), thanks to its tight junctions, limits the
entry of immune cells, notably lymphocytes, into the brain.
Research in neuroimmunology has shown that the brain possesses its
own system of defense, which, in addition to being activated by
immune stimuli, is closely linked to the immune system (figure
1). Inflammatory cytokines, which are important
mediators of communication within the immune system, also act in
the brain, in particular by activating the innate immune cells of
the brain that in turn, produce inflammatory cytokines (Dantzer
et al., 1998). The synthesis of brain cytokines is finely
regulated, allowing them to return to basal levels without leading
either to a rupture of the BBB or to cerebral lesion. On the other
hand, when these factors are synthesized in large quantities or in
a chronic manner by the brain, they have toxic effects on neurons,
resulting in substantial neuronal dysfunction that can lead to cell
death. The alteration of neuronal function induced by cytokine
actions is also seen during aging, where microinflammation,
characterized by microglial reactivity and the chronic production
of low levels of inflammatory cytokines occurs (Laye, 2010). This
microneuroinflammation, which increases the vulnerability of the
aging brain to immune stimuli, is characterized by the increased
production of brain cytokines and the risk of developing delirium
and/or neurodegenerative disorders with an inflammatory component,
such as Alzheimer's disease (Perry et al., 2003).
Accordingly, clinical and epidemiological studies have shown a
correlation between the systemic expression levels of inflammatory
cytokines and the incidence of functional/behavioral alterations
(cognitive or mood disorders) in elderly subjects. In this context,
limiting the development of chronic neuroinflammation represents a
key element in the protection of the brain against
neurodegenerative disorders.
Diet constitutes a strategy of choice for such an approach,
since it represents an environmental factor to which individuals
are exposed throughout their life. Increasing attention has been
paid to omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids
(PUFAs), micronutrients that are essential since they cannot be
synthesized de novo by the organism. An increasing database attests
of the powerful immunomodulatory effects of PUFAs (Calder, 2001).
Thus, n-3 PUFAs form the basis of lipid derivatives
(neuroprotectins and resolvins) with anti-inflammatory properties,
whereas n-6 PUFAs are the precursors of the proinflammatory
prostacyclins, and stimulate the production and activity of
inflammatory cytokines. The brain is extremely rich in PUFAs and
the accumulation of PUFAS in brain tissues takes place during the
perinatal period in proportions which are dependent on maternal
dietary levels. Conversely, their levels diminish as the individual
ages, but can be corrected by appropriate nutritional strategies.
During the last few decades, the lifestyle of Western societies has
evolved towards a decrease in energy expenditure mainly related to
our sedenterization, processes and a changes in our dietary habits
towards the consumption of energy-rich foods with high levels of
saturated fats, n-6 PUFAs and sugar, and poor in vitamins and
micronutrients (Simopoulos, 2001). This dramatic reduction in the
dietary supply of n-3 PUFAs and the corresponding increase in n-6
PUFAs, leading to an imbalanced n-6/n-3 ratio currently estimated
at 12-20 in developed countries (of note, the current recommended
ratio is 5), could therefore contribute to the sensitization of the
brain to inflammatory cytokines, and thus to the development of
neurodegenerative and/or neurobehavioral disorders.
The innate immune system of the brain
Microglial cells are the resident macrophages of the brain, and
constitute the first line of immune defense of the brain
(phagocytosis, antigen presentation and secretion of
proinflammatory cytokines) (Biber et al., 2007). These cells
have a ramified morphology when quiescent and an ameboid morphology
when activated and they produce cytokines. Ramified microglia cells
generally do not display phagocytic activity and weakly express
ligands and receptors involved in macrophage function. Disseminated
throughout the brain parenchyma, they use their processes to
receive signals such as inflammatory cytokines from their
microenvironment, which reveal the existence of a lesion or the
presence of a pathogen. In order to do this, microglial cells
express several membrane receptors, including those for the
inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor
(TNF)-α and IL-6, as well as those that allow the recognition of
PAMPs (pathogen-associated molecular patterns), such as the
bacterial endotoxin receptors Toll-like receptor (TLR)4 and CD14.
Recent evidence indicates that neurons control microglial activity.
As a result, neurons release ON or OFF signals to regulate the
activation of microglia. OFF signals (CD200, CX3CL1, CD47, CD55 and
HMGB1) are produced by healthy neurons to keep microglia in their
surveillance mode. On the opposite, damaged neurons express
inducible ON signals (chemokines, purine and glutamate) to activate
microglia and phagocytosis (Biber et al., 2007).
Interestingly, such neuronal-glial interactions are impaired in the
aged brain leading to amplified and prolonged microglial activation
and production of proinflammatory cytokines (Streit, 2006).
Brain innate immune system in the aging brain
Aging is characterized by a chronic low grade inflammatory state
with a higher expression of proinflammatory cytokines IL-1b,
IL-6 and TNFα to the detriment of anti-inflammatory factors such as
IL-10 and IL-4. This state is called inflammaging at the
periphery and in the brain. Recent clinical and experimental data
obtained in our group have shown a strong association between blood
proinflammatory cytokines levels, especially IL-6, quality of life
and neuropsychiatric symptoms in a cohort of elderly subjects
(Capuron et al., 2009; Capuron et al., 2011) and in
aged laboratory mice (Moranis et al., 2011). The mechanisms
underlying the effect of proinflammatory cytokine on mood and
cognitive disorders have been intensively studied in rodents
(Yirmiya and Goshen, 2011). In the brain, IL-1β, TNFα and IL-6 are
produced by glial cells (microglia and astrocytes) in response to
peripheral immune stimuli like the bacterial endotoxin
lipopolysaccharide (LPS) (Laye et al., 1994). Studies using
minocycline, a tetracycline derivative that inhibits microglial
activation and cytokine production, show a link between brain
cytokine production and depressive-like symptoms as well as spatial
memory impairment (Dantzer et al., 2008). In addition to
impairing the metabolism of serotoninergic and glutamatergic
neurotransmission systems, which are well known players in mood and
cognition respectively, brain proinflammatory cytokines alter
hippocampal synaptic plasticity in adult and aged rodents (Lynch,
1998). Importantly, we recently showed in a population of elderly
subjects, that age-related low-grade systemic inflammation was
associated with alterations in the activity of two enzymatic
pathways, the indoleamine 2,3 dioxygenase (IDO) and
guanosine-triphosphate-cyclohydrolase-1 (GTP-CH1) pathways, which
are involved on in the metabolism of key monoamines (Capuron et
al., 2011) (figure 2).
Interestingly, increased IDO activity was associated with the
depressive symptoms of lassitude, reduced motivation, anorexia, and
pessimism in the same population. In contrast, decreased GTP-CH1
activity correlated more with neurovegetative symptoms, including
sleep disturbance, digestive symptoms, fatigue, sickness, and motor
symptoms.
IL-1 overexpression has been implicated in both the initiation
and progression of neuropathological changes (Rothwell and Luheshi,
2000). Accordingly, overexpression of IL-1 in the Alzheimer brain
has been linked to an increased microglial activity, frequently
associated with amyloid plaques. 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. In addition, brain
from Tg2576 mice (a model of Alzheimer disease) exhibited
significant increases in IL-1 expression in comparison to healthy
animals. Moreover, aged Tg2576 showed mounted and exacerbated
cytokine response to LPS, a process that may be responsible for the
amplification of degenerative processes. IL-1 administration was
found to diminish food intake in a greater extent in aged mice
compared to adults.
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, which could explain the cognitive impairment
observed in the elderly. Receptors for IL-1 are distributed with a
high density in the hippocampus, where IL-1 exerts inhibitory
effects on the release of calcium. There is also evidence for a
role of endogenous brain IL-1 in the normal physiological
regulation of hippocampal plasticity and learning processes (Lynch,
1998). Low levels of IL-1 are essential for memory and plasticity,
whereas higher levels of IL-1, similar to those achieved during
aging and neurodegeneration, can be detrimental.
Polyunsaturated fatty acids and their role in the control of
innate cerebral immunity and its behavioral effects
PUFAs of the n-3 or n-6 families are essential nutriments, as
they cannot be generated de novo in mammals. In plants, they exist
as precursors (linoleic acid (18:2n-6, LA) and α-linolenic acid
(18:3n-3, ALA)) that are metabolized by a series of elongation and
desaturation steps into arachidonic acid (20:4n-6, AA) in the first
case and eicosapentaenoic acid (20:5 n-3, EPA) and docosahexaenoic
acid (22:6 n-3, DHA) in the second. These PUFAs are incorporated
into cell membranes as phospholipids. The liver is the principal
site of conversion of the precursors LA and ALA into long-chain
PUFAs, although other organs such as the brain also express the
necessary elongases and desaturases. Since the two series of PUFAs
compete for the use of the enzymes necessary for their
biosynthesis, and because they have distinct physiological
properties, the n-6/n-3 ratio in the diet is of particular
importance. Foods that were previously consumed by humans were rich
in n-3 PUFAs (products of hunting), while those consumed today are
poor in these nutrients. Since the industrial revolution, the ratio
of n-6/n-3 PUFAs in the diet has increased from 1 to almost 20 in
industrialized countries like the United States, leading to a
significant deficiency in n-3 PUFAs (Simopoulos, 2006).
The dietary deficiency in n-3 PUFAs is associated with
significant decreases in PUFAs intracerebral levels, promoting thus
neuroinflammatory processes and the subsequent development of
inflammatory-based CNS disorders (Laye, 2010). Supporting this
notion is the low very incidence of inflammatory disorders (e.g.,
psoriasis, asthma, multiple sclerosis) in populations, such as
Greenland Inuits, with a high n-3 PUFAs dietary intake due to
elevated fish consumption. The effect of n-3 supplementation is
currently subject to debate. While some clinical studies have
reported anti-inflammatory effects of n-3 PUFAs administered in the
context of chronic and autoimmune inflammatory disorders, other
reports fail to reproduce these findings. Conversely, dietary
supplementation with fish oil rich in long chain n-3 derivatives,
including EPA and DHA, leads to an improvement in symptoms in
patients with rheumatoid arthritis, chronic inflammatory intestinal
disorders or multiple sclerosis (Calder, 2006).
Consequences of the decrease in n-3 PUFAs on age-related
neuroinflammation
Experiments conducted in animals have highlighted brain DHA as a
potent mediator of the protective effects of dietary n-3 PUFAs.
Because it cannot be synthesized de novo in mammalian cells, brain
DHA must be provided in the diet, either in the form of its
precursor α-linolenic acid (α-LNA, 18:3n-3) or in the form of DHA.
Low dietary intake of n-3 PUFA decreases DHA levels in the animal
brain. As a result, emotional behavior (depressive-like symptoms
and anxiety) as well as learning and memory are impaired as shown
by us and others (Fedorova and Salem, 2006; Lafourcade et
al., 2011; Moranis et al., 2011). On the opposite,
positive effects of diet enriched in DHA on learning and memory
have been demonstrated in laboratory animals (Gamoh et al.,
1999; Yehuda et al., 1999; Carrie et al., 2002).
During aging, the level and replacement of brain PUFAs decreases,
particularly in the hippocampus, cortex, striatum and hypothalamus
(figure
3). Brain levels of DHA and AA diminish in aging
rats who display alterations in cognition and in LTP in the
hippocampus (Favreliere et al., 2003). In transgenic SAMP8
mice, in which aging is accelerated, DHA decreases with age whereas
lipid peroxidation increases (Petursdottir et al., 2002). In
addition, the conversion of the precursors LA and ALA into their
long-chain derivatives becomes less efficient. In fact, the
activity of the desaturases responsible for the conversion of LA
and ALA into their respective long-chain derivatives, and the
activity of the Δ6 desaturase in particular, decreases with age in
the liver and the brain. Phospholipid synthesis pathways are also
altered with age, thus reducing the incorporation of PUFAs into
membranes. The combination and interaction of these different
alterations associated with aging contributes to a reduction in the
level of DHA, i.e. a reduction in the index of membrane fluidity,
in the brain of elderly people. In animals, aging was found to be
associated with a decrease in the membrane content of AA in the
hippocampus together with an attenuation of long term potentiation
(LTP) that can be reestablished by a diet containing AA (McGahon
et al., 1999). These data support the idea of the importance
of DHA dietary supply in aged subjects (figure
3).
As mentioned above, PUFAs represent potent immunomodulatory
agents. We have recently demonstrated in vitro that the
production of IL-1β and TNFα by murine microglia induced by LPS was
strongly inhibited by DHA through its effect on LPS signaling
pathway Nuclear Factor κ B (De Smedt-Peyrusse et al., 2008).
In vivo, chronic dietary n-3 PUFA deficiency significantly
increased the production and release of IL-6 and TNFα in the blood
(McNamara et al., 2010). In addition, mice exposed
throughout life to a diet devoid of n-3 PUFAs displayed lower brain
DHA level and higher LPS-induced IL-6 in the plasma and in the
hippocampus (Mingam et al., 2008). With aging, IL-6
expression was increased in the cortex of both n-3 deficient and
n-3 adequate mice while IL-10 expression was decreased with no
effect of long term α-LNA deficient or enriched diet (Moranis et
al., 2011) (figure 4).
On the opposite, short term exposure to dietary EPA reduced
IL-1-induced spatial memory deficit and anxiolytic behavior (Song
et al., 2004; Song et al., 2008) and improved LPS and
Aβ-induced inhibition of long term potentiation (LTP) in both adult
and aged rats (Minogue et al., 2007). The expression of
markers of microglial activation (CD68, MHCII and CD11b) increases
with age in animals, as does the number of microglia in the brain
of humans, attesting of the occurrence of age-related
neuroinflammation (Godbout et al., 2005). Microglial cell
reactivity is involved in the age-dependant increase in the
production of inflammatory cytokines, as demonstrated by the
inhibition of inflammatory cytokine overexpression by minocycline
in aged rats (Griffin et al., 2006). In a cohort of elderly
subjects, depressive individuals with an elevated plasma n-6/n-3
ratio were found to exhibit higher levels of TNFα and of IL-6
(Kiecolt-Glaser et al., 2007). Additionally, n-3 PUFA
supplementation in elderly subjects reduced the levels of
inflammatory cytokines produced by blood leukocytes stimulated
in vitro (Meydani et al., 1991). The production of
PGE2 by monocytes is inversely correlated to the EPA content of
leukocytes obtained from aged subjects after the consumption of
dietary complements containing different doses of EPA (Rees et
al., 2006). In rats, microglial activation, production of IL-1β
and alterations in hippocampal LTP with age were attenuated by EPA
(Lynch et al., 2007). To the extent that the level of
peripheral cytokines reflects that of cytokines in the brain, these
results suggest that dietary n-3 PUFAs modulate neuroinflammation
and associated neurobehavioral effects in elderly individuals
(Laye, 2010).
Epidemiological studies reveal the importance of n-3 PUFA levels
in the development of age-linked neurodegenerative disorders. Thus,
decreases in plasma and brain DHA levels have been shown in
patients with Alzheimer's disease. These results, however, remain
controversial, since other studies have demonstrated an increase or
an absence of variation in brain DHA levels in similar populations.
Nonetheless, the risk of dementia was found to be augmented in
elderly subjects presenting low levels of circulating EPA (Samieri
et al., 2011). In addition, regular consumption of diets
rich in n-3 PUFA, such as the Mediterranean diet, appears to
contribute to a decrease in the risk of depression and/or dementia
in the elderly (Feart et al., 2008; Feart et al.,
2011). The use of a mouse model of Alzheimer's disease, the Tg2576
mouse, has demonstrated that a dietary supply of DHA leads to a
reduction in the formation of amyloid plaques. However, the
administration of dietary supplements containing DHA to patients
with Alzheimer's disease or mild cognitive impairment has not
yielded conclusive results (Calon and Cole, 2007).
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 mood and cognitive disorders
during the host response to infection, but also during chronic
inflammatory states and aging. 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
effects on inflammation and cell functions, PUFAs definitely play a
role in this process. However, this role needs to be better
characterized by multidisciplinary studies aimed at assessing the
effects of these molecules at different levels, from the molecular
level to that of the organism as a whole.
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