Feeding Our Immune System: Impact on Metabolism

Endogenous intestinal microflora and environmental factors, such as diet, play a central role in immune homeostasis and reactivity. In addition, microflora and diet both influence body weight and insulin-resistance, notably through an action on adipose cells. Moreover, it is known since a long time that any disturbance in metabolism, like obesity, is associated with immune alteration, for example, inflammation. The purpose of this review is to provide an update on how nutrients-derived factors (mostly focusing on fatty acids and glucose) impact the innate and acquired immune systems, including the gut immune system and its associated bacterial flora. We will try to show the reader how the highly energy-demanding immune cells use glucose as a main source of fuel in a way similar to that of insulin-responsive adipose tissue and how Toll-like receptors (TLRs) of the innate immune system, which are found on immune cells, intestinal cells, and adipocytes, are presently viewed as essential actors in the complex balance ensuring bodily immune and metabolic health. Understanding more about these links will surely help to study and understand in a more fundamental way the common observation that eating healthy will keep you and your immune system healthy

Interleukin-7, a New Cytokine Targeting the Mouse Hypothalamic Arcuate Nucleus: Role in Body Weight and Food Intake Regulation

Body weight is controlled through peripheral (white adipose tissue) and central (mainly hypothalamus) mechanisms. We have recently obtained evidence that overexpression of interleukin (IL)-7, a critical cytokine involved in lymphopoiesis, can protect against the development of diet-induced obesity in mice. Here we assessed whether IL-7 mediated its effects by modulating hypothalamic function. Acute subcutaneous injection of IL-7 prevented monosodium glutamate-induced obesity, this being correlated with partial protection against cell death in the hypothalamic arcuate nucleus (ARC). Moreover, we showed that IL-7 activated hypothalamic areas involved in regulation of feeding behavior, as indicated by induction of the activation marker c-Fos in neural cells located in the ventromedial part of the ARC and by inhibition of food intake after fasting. Both chains of the IL-7 receptor (IL-7Rα and γc) were expressed in the ARC and IL-7 injection induced STAT-3 phosphorylation in this area. Finally, we established that IL-7 modulated the expression of neuropeptides that tune food intake, with a stimulatory effect on the expression of pro-opiomelanocortin and an inhibitory effect on agouti-related peptide expression in accordance with IL-7 promoting anorectic effects. These results suggest that the immunomodulatory cytokine IL-7 plays an important and unappreciated role in hypothalamic body weight regulation

Gut dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production

Secondary bacterial infections often complicate viral respiratory infections. We hypothesize that perturbation of the gut microbiota during influenza A virus (IAV) infection might favor respiratory bacterial superinfection. Sublethal infection with influenza transiently alters the composition and fermentative activity of the gut microbiota in mice. These changes are attributed in part to reduced food consumption. Fecal transfer experiments demonstrate that the IAV-conditioned microbiota compromises lung defenses against pneumococcal infection. In mechanistic terms, reduced production of the predominant short-chain fatty acid (SCFA) acetate affects the bactericidal activity of alveolar macrophages. Following treatment with acetate, mice colonized with the IAV-conditioned microbiota display reduced bacterial loads. In the context of influenza infection, acetate supplementation reduces, in a free fatty acid receptor 2 (FFAR2)-dependent manner, local and systemic bacterial loads. This translates into reduced lung pathology and improved survival rates of double-infected mice. Lastly, pharmacological activation of the SCFA receptor FFAR2 during influenza reduces bacterial superinfection

Interleukin-7 Regulates Adipose Tissue Mass and Insulin Sensitivity in High-Fat Diet-Fed Mice through Lymphocyte-Dependent and Independent Mechanisms

Although interleukin (IL)-7 is mostly known as a key regulator of lymphocyte homeostasis, we recently demonstrated that it also contributes to body weight regulation through a hypothalamic control. Previous studies have shown that IL-7 is produced by the human obese white adipose tissue (WAT) yet its potential role on WAT development and function in obesity remains unknown. Here, we first show that transgenic mice overexpressing IL-7 have reduced adipose tissue mass associated with glucose and insulin resistance. Moreover, in the high-fat diet (HFD)-induced obesity model, a single administration of IL-7 to C57BL/6 mice is sufficient to prevent HFD-induced WAT mass increase and glucose intolerance. This metabolic protective effect is accompanied by a significant decreased inflammation in WAT. In lymphocyte-deficient HFD-fed SCID mice, IL-7 injection still protects from WAT mass gain. However, IL-7-triggered resistance against WAT inflammation and glucose intolerance is lost in SCID mice. These results suggest that IL-7 regulates adipose tissue mass through a lymphocyte-independent mechanism while its protective role on glucose homeostasis would be relayed by immune cells that participate to WAT inflammation. Our observations establish a key role for IL-7 in the complex mechanisms by which immune mediators modulate metabolic functions

Determination et analyse des epitopes T fonctionnels de l'antigene protecteur Sm28GST du parasite trematode Schistosoma mansoni

SIGLEINIST T 77304 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

The role of S1P4 in the immune system

La signalisation par le sphingosine 1-phosphate (S1P) joue un rôle régulateur dans le système immunitaire. Parmi les récepteurs du S1P, S1P1 et S1P4 sont ceux majoritairement exprimés par de nombreux types de cellules immunes. Alors que S1P1 est connu pour ses fonctions in vivo, le rôle fonctionnel de S1P4 dans le système immunitaire n'a pas encore été élucidé. Nous avons donc caractérisé le système immunitaire des souris déficientes en S1P4. Tout d'abord, nous montrons que la composition cellulaire dans les organes lymphoïdes primaires et secondaires ainsi que dans le sang ne montre que de faibles différences. Par contre, les quantités d'IgG1, d'IgA et d'IgE plasmatiques sont plus élevées chez les souris S1P4-/-. L'analyse détaillée du compartiment B montre une augmentation significative de 70% des MZ B-lymphocytes. Comme le profil des immunoglobulines plasmatiques indique une réponse cellulaire orientée TH2, la fonctionnalité a été testée dans des modèles d'asthme, de réaction d'hypersensibilité retardée et d'hypersensibilité de contact, confirmant l'orientation préférentielle de type TH2 chez les animaux S1P4-/-. De plus, nous montrons que S1P4 joue un rôle dans la migration des lymphocytes T. Un effet compensatoire de S1P1 dans le modèle S1P4-/- ne pouvait être exclu. Afin d'évaluer l'éventuelle redondance des fonctions de S1P1 et S1P4, nous avons généré un vecteur lentiviral pour l'inhibition de l'expression de S1P1 par des petits ARN à interférence (siRNA). Ceci permettra d'obtenir un modèle de souris déficiente pour les deux types de récepteurs sur les cellules hématopoïétiques et donc de mieux discerner les fonctions respectives de S1P1 et S1P4 in vivo.LILLE1-BU (590092102) / SudocSudocFranceF

Influenza A Virus Infection Induces White Adipose Tissue Browning: A Metabolic Adaptation to Infection?

International audienceWe recently reported that influenza infection is associated with drastic, depot-specific changes in white adipose tissue (WAT), notably the occurrence of thermogenic brown-like adipocytes within the subcutaneous depot, a process referred to as WAT browning. In mammals, induction of the thermogenic circuit increases heat production and consumes energy, consequently improving host’s metabolism. Importantly, we also demonstrated that mouse and human preadipocytes commit to the thermogenic differentiation program upon in vitro influenza virus infection; this signifies that infection-associated WAT browning may partly rely on a direct effect of the virus on fat.Herein, after a short review of the physiological and cellular mechanisms that have been described to regulate WAT browning, including immune-cell-dependent ones, we will comment on the role that white adipose tissue, which is at the crossroads of metabolism and immunity, may play in influenza pathophysiology