Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission

Unravelling the sex-specific diversity and functions of adrenal gland macrophages

Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We define the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and use genetic models to explore the developmental mechanisms yielding macrophage diversity. We define populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identify a female-specific subset with low major histocompatibility complex (MHC) class II expression. In adulthood, monocyte recruitment dominates adrenal gland macrophage maintenance in female mice. Adrenal gland macrophage sub-tissular distribution follows a sex-dimorphic pattern, with MHC class IIlow macrophages located at the cortico-medullary junction. Macrophage sex dimorphism depends on the presence of the cortical X-zone. Adrenal gland macrophage depletion results in altered tissue homeostasis, modulated lipid metabolism, and decreased local aldosterone production during stress exposure. Overall, these data reveal the heterogeneity of adrenal gland macrophages and point toward sex-restricted distribution and functions of these cells.</p

Adipose tissue lipolysis controls monocyte homeostasis

Les monocytes font partie des acteurs majeurs de l’immunité innée. Ils sont générés dans la moelle osseuse et contribuent à garantir le maintien de l’homéostasie de l’organisme en cas de blessure ou d’inflammation chronique par leur mobilisation dans le sang et leur recrutement dans les tissus où ils ont la capacité de se différencier en macrophages. Depuis les années 1970, l’étude du contrôle exercé par le métabolisme sur la survie, la fonction et le devenir des cellules immunitaires, et plus particulièrement des macrophages, impliqués dans de nombreuses pathologies cardio-métaboliques, a gagné un grand intérêt auprès de la communauté scientifique. Cependant, les données recueillies sur l’impact du métabolisme sur les monocytes restent très limitées. De façon intéressante à l’état physiologique, le nombre de monocytes dans la circulation sanguine varie au cours de la journée. De plus, nous avons mis en évidence une corrélation entre le nombre de monocytes présents dans la circulation et les taux d’acides gras circulants au cours de la journée. Ainsi, durant ma thèse je me suis intéressée à l’étude de la potentielle causalité qui unit ces deux phénomènes et plus particulièrement à l’impact des métabolites énergétiques tels que les acides gras sur le contrôle des monocytes. Pour ce faire, nous avons utilisé un modèle murin génétiquement déficient pour l’enzyme clé responsable de la libération des acides gras à travers la lipolyse du tissu adipeux, appelée Atgl. Nous avons pu mettre en évidence que l’altération de la lipolyse du tissu adipeux entraine un stress et une inflammation chronique spécifique du tissu adipeux brun, associés à un recrutement local massif des monocytes de façon dépendante de l’expression du récepteur aux chimiokines CCR2. Le recrutement accru des monocytes dans le tissu adipeux brun est également associé à une diminution des taux de monocytes dans la circulation sanguine. Cependant chez ces souris, nous n’avons pas observé d’altération du compartiment médullaire, siège de l’hématopoïèse et de la production des cellules sanguines. Nos résultats permettent ainsi de mettre en évidence l’importance de la lipolyse ainsi que du recrutement des monocytes sur le maintien de l’homéostasie du tissu adipeux brun.Monocytes are key players in innate immunity mechanisms. They originate from the bone marrow and contribute to the whole-body homeostasis maintenance by being mobilized to the blood circulation in case of injury or chronic inflammation for example. There, monocytes can either stay in the blood circulation, or be recruited to peripheral tissues where they can differentiate into macrophages. Since the 70’s the metabolic control of immune cell survival, function and fate, mostly in macrophages that are involved in numerous cardio-metabolic diseases, gained great interest from the scientific community. However, the monocyte-specific metabolic control is still ill-defined. Interestingly, in steady state, blood monocyte numbers oscillate throughout the day on a 24h basis. Moreover, we highlighted a correlation between circulating monocyte number oscillation pattern and fatty acid levels during the day. Therefore, during my Ph.D. I focused on deciphering the possible causality that unites those phenomena and more particularly on studying the impact of energetic metabolites such as fatty acids on the control of monocytes. In this purpose, we generated a genetic mouse model deficient for the lipolysis adipose tissue key enzyme, namely Atgl. Here, we show that the inhibition of adipose tissue lipolysis leads to stress and specific chronic inflammation in the brown adipose tissue, associated to a local monocyte recruitment in a CCR2-dependant manner. This brown adipose tissue monocyte recruitment was paralleled to a decrease in blood monocyte numbers. However, we failed to see alterations in the bone marrow compartment, responsible for hematopoiesis and blood cell production. Thus, we highlighted the major role of adipose tissue lipolysis and monocyte recruitment on brown adipose tissue homeostasis

Importance de la lipolyse adipocytaire dans le contrôle de l’homéostasie des monocytes

Monocytes are key players in innate immunity mechanisms. They originate from the bone marrow and contribute to the whole-body homeostasis maintenance by being mobilized to the blood circulation in case of injury or chronic inflammation for example. There, monocytes can either stay in the blood circulation, or be recruited to peripheral tissues where they can differentiate into macrophages. Since the 70’s the metabolic control of immune cell survival, function and fate, mostly in macrophages that are involved in numerous cardio-metabolic diseases, gained great interest from the scientific community. However, the monocyte-specific metabolic control is still ill-defined. Interestingly, in steady state, blood monocyte numbers oscillate throughout the day on a 24h basis. Moreover, we highlighted a correlation between circulating monocyte number oscillation pattern and fatty acid levels during the day. Therefore, during my Ph.D. I focused on deciphering the possible causality that unites those phenomena and more particularly on studying the impact of energetic metabolites such as fatty acids on the control of monocytes. In this purpose, we generated a genetic mouse model deficient for the lipolysis adipose tissue key enzyme, namely Atgl. Here, we show that the inhibition of adipose tissue lipolysis leads to stress and specific chronic inflammation in the brown adipose tissue, associated to a local monocyte recruitment in a CCR2-dependant manner. This brown adipose tissue monocyte recruitment was paralleled to a decrease in blood monocyte numbers. However, we failed to see alterations in the bone marrow compartment, responsible for hematopoiesis and blood cell production. Thus, we highlighted the major role of adipose tissue lipolysis and monocyte recruitment on brown adipose tissue homeostasis.Les monocytes font partie des acteurs majeurs de l’immunité innée. Ils sont générés dans la moelle osseuse et contribuent à garantir le maintien de l’homéostasie de l’organisme en cas de blessure ou d’inflammation chronique par leur mobilisation dans le sang et leur recrutement dans les tissus où ils ont la capacité de se différencier en macrophages. Depuis les années 1970, l’étude du contrôle exercé par le métabolisme sur la survie, la fonction et le devenir des cellules immunitaires, et plus particulièrement des macrophages, impliqués dans de nombreuses pathologies cardio-métaboliques, a gagné un grand intérêt auprès de la communauté scientifique. Cependant, les données recueillies sur l’impact du métabolisme sur les monocytes restent très limitées. De façon intéressante à l’état physiologique, le nombre de monocytes dans la circulation sanguine varie au cours de la journée. De plus, nous avons mis en évidence une corrélation entre le nombre de monocytes présents dans la circulation et les taux d’acides gras circulants au cours de la journée. Ainsi, durant ma thèse je me suis intéressée à l’étude de la potentielle causalité qui unit ces deux phénomènes et plus particulièrement à l’impact des métabolites énergétiques tels que les acides gras sur le contrôle des monocytes. Pour ce faire, nous avons utilisé un modèle murin génétiquement déficient pour l’enzyme clé responsable de la libération des acides gras à travers la lipolyse du tissu adipeux, appelée Atgl. Nous avons pu mettre en évidence que l’altération de la lipolyse du tissu adipeux entraine un stress et une inflammation chronique spécifique du tissu adipeux brun, associés à un recrutement local massif des monocytes de façon dépendante de l’expression du récepteur aux chimiokines CCR2. Le recrutement accru des monocytes dans le tissu adipeux brun est également associé à une diminution des taux de monocytes dans la circulation sanguine. Cependant chez ces souris, nous n’avons pas observé d’altération du compartiment médullaire, siège de l’hématopoïèse et de la production des cellules sanguines. Nos résultats permettent ainsi de mettre en évidence l’importance de la lipolyse ainsi que du recrutement des monocytes sur le maintien de l’homéostasie du tissu adipeux brun

Metabolism Plays a Key Role during Macrophage Activation

Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key roles in controlling tissue homeostasis, infections, and excessive inflammation. Macrophages remove dead cells in a process named efferocytosis, contributing to the healthy tissue maintenance. Recently, it became clear that the main macrophage functions are under metabolic control. Modulation of glucose, fatty acid, and amino acid metabolism is associated with various macrophage activations in response to external stimuli. Deciphering these metabolic pathways provided critical information about macrophage functions

A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies

International audienceSCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS. We used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling. Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes

Brown adipose tissue monocytes support tissue expansion

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling

Brown adipose tissue monocytes support tissue expansion

International audienceMonocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling

Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal that glutaminase (GLS) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (GLUD1) to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and human

Brown adipose tissue monocytes support tissue expansion

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling. Adipose tissue is composed of a number of adipocytes and a number of other cells including immune cells. Here the authors use single-cell sequencing of murine brown adipose tissue immune cells and describe multiple macrophage and monocyte subsets and show that monocytes contribute to brown adipose tissue expansion