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03/10/2017 | Prog Neuropsychopharmacol Biol Psychiatry   IF 4.2
Bioactive lipids as new class of microglial modulators: When nutrition meets neuroimunology.
Nadjar A, Leyrolle Q, Joffre C, Laye S

Within the central nervous system the traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. More recently, microglia have been found to be important for normal brain development, circuit refinement, and synaptic plasticity in ways that were previously unsuspected. Hence, the brain innate immune system appears to be key in all situations, ranging from physiology to pathology. This unique feature of microglia is established by the wide array of receptors it is equipped with to sense molecular patterns. This includes receptors to most if not all neurotransmitters, neuromodulators and purines. We here review novel, yet extensive literature on a new class of microglia modulators, namely bioactive fatty acids. These lipids are issued from metabolism of nutrients and can cross the blood brain barrier to reach the CNS. They appear to be direct modulators of microglial activity, triggering/inhibiting inflammatory processes or enhancing/inhibiting the ability of these cells to respond to hazardous agents.

2017 | Front Cell Neurosci   IF 4.6
Roles of Microglial Phagocytosis and Inflammatory Mediators in the Pathophysiology of Sleep Disorders.
Nadjar A, Wigren HM, Tremblay ME

Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation.

11/2016 | Prostaglandins Leukot Essent Fatty Acids   IF 3.2
Modulation of brain PUFA content in different experimental models of mice.
Joffre C, Gregoire S, De Smedt V, Acar N, Bretillon L, Nadjar A, Laye S

The relative amounts of arachidonic acid (AA) and docosahexaenoic acid (DHA) govern the different functions of the brain. Their brain levels depend on structures considered, on fatty acid dietary supply and the age of animals. To have a better overview of the different models available in the literature we here compared the brain fatty acid composition in various mice models (C57BL/6J, CD1, Fat-1, SAMP8 mice) fed with different n-3 PUFA diets (deficient, balanced, enriched) in adults and aged animals. Our results demonstrated that brain AA and DHA content is 1) structure-dependent; 2) strain-specific; 3) differently affected by dietary approaches when compared to genetic model of PUFA modulation; 4) different in n-3 PUFA deficient aged C57BL6/J when compared to SAMP8 mouse model of aging. From these experiments, we highlight the difficulty to compare results obtained in different mouse models, different strains, different brain regions and different ages.

10/2016 | Prostaglandins Leukot Essent Fatty Acids   IF 3.2
Enriched dairy fat matrix diet prevents early life lipopolysaccharide-induced spatial memory impairment at adulthood.
Dinel AL, Rey C, Baudry C, Fressange-Mazda C, Le Ruyet P, Nadjar A, Pallet P, Joffre C, Laye S

Polyunsaturated fatty acids (PUFAs) are essential fatty acids, which are critical for brain development and later life cognitive functions. The main brain PUFAs are docosahexaenoic acid (DHA) for the n-3 family and arachidonic acid (ARA) for the n-6 family, which are provided to the post-natal brain by breast milk or infant formula. Recently, the use of dairy lipids (DL) in replacement of vegetable lipids (VL) was revealed to potently promote the accretion of DHA in the developing brain. Brain DHA, in addition to be a key component of brain development, display potent anti-inflammatory activities, which protect the brain from adverse inflammatory events. In this work, we evaluated the protective effect of partial replacement of VL by DL, supplemented or not with DHA and ARA, on post-natal inflammation and its consequence on memory. Mice were fed with diets poor in vegetal n-3 PUFA (Def VL), balanced in vegetal n-3/n-6 PUFA (Bal VL), balanced in dairy lipids (Bal DL) or enriched in DHA and ARA (Supp VL; Supp DL) from the first day of gestation until adulthood. At post-natal day 14 (PND14), pups received a single administration of the endotoxin lipopolysaccharide (LPS) and brain cytokine expression, microglia phenotype and neurogenesis were measured. In a second set of experiments, memory and neurogenesis were measured at adulthood. Overall, our data showed that lipid quality of the diet modulates early life LPS effect on microglia phenotype, brain cytokine expression and neurogenesis at PND14 and memory at adulthood. In particular, Bal DL diet protects from the adverse effect of early life LPS exposure on PND14 neurogenesis and adult spatial memory.

09/2016 | PLoS Biol   IF 8.7
Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.
Abiega O, Beccari S, Diaz-Aparicio I, Nadjar A, Laye S, Leyrolle Q, Gomez-Nicola D, Domercq M, Perez-Samartin A, Sanchez-Zafra V, Paris I, Valero J, Savage JC, Hui CW, Tremblay ME, Deudero JJ, Brewster AL, Anderson AE, Zaldumbide L, Galbarriatu L, Marinas A, Vivanco MD, Matute C, Maletic-Savatic M, Encinas JM, Sierra A

[This corrects the article DOI: 10.1371/journal.pbio.1002466.].

07/2016 | Brain Behav Immun   IF 5.9
Resolvin D1 and E1 promote resolution of inflammation in microglial cells in vitro.
Rey C, Nadjar A, Buaud B, Vaysse C, Aubert A, Pallet V, Laye S, Joffre C

Sustained inflammation in the brain together with microglia activation can lead to neuronal damage. Hence limiting brain inflammation and activation of microglia is a real therapeutic strategy for inflammatory disease. Resolvin D1 (RvD1) and resolvin E1 (RvE1) derived from n-3 long chain polyunsaturated fatty acids are promising therapeutic compounds since they actively turn off the systemic inflammatory response. We thus evaluated the anti-inflammatory activities of RvD1 and RvE1 in microglia cells in vitro. BV2 cells were pre-incubated with RvD1 or RvE1 before lipopolysaccharide (LPS) treatment. RvD1 and RvE1 both decreased LPS-induced proinflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) gene expression, suggesting their proresolutive activity in microglia. However, the mechanisms involved are distinct as RvE1 regulates NFkappaB signaling pathway and RvD1 regulates miRNAs expression. Overall, our findings support that pro-resolving lipids are involved in the resolution of brain inflammation and can be considered as promising therapeutic agents for brain inflammation.

05/2016 | PLoS Biol   IF 8.7
Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.
Abiega O, Beccari S, Diaz-Aparicio I, Nadjar A, Laye S, Leyrolle Q, Gomez-Nicola D, Domercq M, Perez-Samartin A, Sanchez-Zafra V, Paris I, Valero J, Savage JC, Hui CW, Tremblay ME, Deudero JJ, Brewster AL, Anderson AE, Zaldumbide L, Galbarriatu L, Marinas A, Vivanco Md, Matute C, Maletic-Savatic M, Encinas JM, Sierra A

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.

2016 | neural plast   IF 3.6
Neuroinflammation in Autism: Plausible Role of Maternal Inflammation, Dietary Omega 3, and Microbiota.
Madore C, Leyrolle Q, Lacabanne C, Benmamar-Badel A, Joffre C, Nadjar A, Laye S

Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology.

11/2015 | Neuropsychopharmacology   IF 7
Dietary n-3 PUFAs Deficiency Increases Vulnerability to Inflammation-Induced Spatial Memory Impairment.
Delpech JC, Thomazeau A, Madore C, Bosch-Bouju C, Larrieu T, Lacabanne C, Remus-Borel J, Aubert A, Joffre C, Nadjar A, Laye S

Dietary n-3 polyunsaturated fatty acids (PUFAs) are critical components of inflammatory response and memory impairment. However, the mechanisms underlying the sensitizing effects of low n-3 PUFAs in the brain for the development of memory impairment following inflammation are still poorly understood. In this study, we examined how a 2-month n-3 PUFAs deficiency from pre-puberty to adulthood could increase vulnerability to the effect of inflammatory event on spatial memory in mice. Mice were given diets balanced or deficient in n-3 PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS), a bacterial endotoxin, at adulthood. We first showed that spatial memory performance was altered after LPS challenge only in n-3 PUFA-deficient mice that displayed lower n-3/n-6 PUFA ratio in the hippocampus. Importantly, long-term depression (LTD), but not long-term potentiation (LTP) was impaired in the hippocampus of LPS-treated n-3 PUFA-deficient mice. Proinflammatory cytokine levels were increased in the plasma of both n-3 PUFA-deficient and n-3 PUFA-balanced mice. However, only n-3 PUFA-balanced mice showed an increase in cytokine expression in the hippocampus in response to LPS. In addition, n-3 PUFA-deficient mice displayed higher glucocorticoid levels in response to LPS as compared with n-3 PUFA-balanced mice. These results indicate a role for n-3 PUFA imbalance in the sensitization of the hippocampal synaptic plasticity to inflammatory stimuli, which is likely to contribute to spatial memory impairment.

09/2015 | Neuropharmacology   IF 5.1
Microglia in neuronal plasticity: Influence of stress.
Delpech JC, Madore C, Nadjar A, Joffre C, Wohleb ES, Laye S

The central nervous system (CNS) has previously been regarded as an immune-privileged site with the absence of immune cell responses but this dogma was not entirely true. Microglia are the brain innate immune cells and recent findings indicate that they participate both in CNS disease and infection as well as facilitate normal CNS function. Microglia are highly plastic and play integral roles in sculpting the structure of the CNS, refining neuronal circuitry and connectivity, and contribute actively to neuronal plasticity in the healthy brain. Interestingly, psychological stress can perturb the function of microglia in association with an impaired neuronal plasticity and the development of emotional behavior alterations. As a result it seemed important to describe in this review some findings indicating that the stress-induced microglia dysfunction may underlie neuroplasticity deficits associated to many mood disorders. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.