Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages

Objective Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1β-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1β-induced microcrystal response. Methods Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1β production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition. Results We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1β production, and microcrystal inflammation in vivo. Conclusion In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1β response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation

Valsartan Improves Adipose Tissue Function in Humans with Impaired Glucose Metabolism: A Randomized Placebo-Controlled Double-Blind Trial

<div><h3>Background</h3><p>Blockade of the renin-angiotensin system (RAS) reduces the incidence of type 2 diabetes mellitus. In rodents, it has been demonstrated that RAS blockade improved adipose tissue (AT) function and glucose homeostasis. However, the effects of long-term RAS blockade on AT function have not been investigated in humans. Therefore, we examined whether 26-wks treatment with the angiotensin II type 1 receptor blocker valsartan affects AT function in humans with impaired glucose metabolism (IGM).</p> <h3>Methodology/Principal Findings</h3><p>We performed a randomized, double-blind, placebo-controlled parallel-group study, in which 38 subjects with IGM were treated with valsartan (VAL, 320 mg/d) or placebo (PLB) for 26 weeks. Before and after treatment, an abdominal subcutaneous AT biopsy was collected for measurement of adipocyte size and AT gene/protein expression of angiogenesis/capillarization, adipogenesis, lipolytic and inflammatory cell markers. Furthermore, we evaluated fasting and postprandial AT blood flow (ATBF) (¹³³Xe wash-out), systemic inflammation and insulin sensitivity (hyperinsulinemic-euglycemic clamp). VAL treatment markedly reduced adipocyte size (<em>P</em><0.001), with a shift toward a higher proportion of small adipocytes. In addition, fasting (<em>P</em> = 0.043) and postprandial ATBF (<em>P</em> = 0.049) were increased, whereas gene expression of angiogenesis/capillarization, adipogenesis and macrophage infiltration markers in AT was significantly decreased after VAL compared with PLB treatment. Interestingly, the change in adipocyte size was associated with alterations in insulin sensitivity and reduced AT gene expression of macrophage infiltration markers. VAL did not alter plasma monocyte-chemoattractant protein (MCP)-1, TNF-α, adiponectin and leptin concentrations.</p> <h3>Conclusions/Significance</h3><p>26-wks VAL treatment markedly reduced abdominal subcutaneous adipocyte size and AT macrophage infiltration markers, and increased ATBF in IGM subjects. The VAL-induced decrease in adipocyte size was associated with reduced expression of macrophage infiltration markers in AT. Our findings suggest that interventions targeting the RAS may improve AT function, thereby contributing to a reduced risk of developing cardiovascular disease and type 2 diabetes.</p> <h3>Trial Registration</h3><p>Trialregister.nl NTR721 (ISRCTN Registry: ISRCTN<a href="http://www.controlled-trials.com/isrctn/pf/42786336">42786336</a>)</p> </div

Etude du rôle << Liver Receptor Homolog-1 >> dans la régulation de la réponse inflammatoire hépatique et dans l'homéostasie du cholestérol

Etude du rôle de Liver Receptor Homolog-1 (LRH-1 ; NR5A2) dans la régulation de la réponse inflammatoire hépatique et dans l homéostasie du cholestérol Les récepteurs nucléaires sont des facteurs de transcription impliqués dans des processus biologiques cruciaux tels que la reproduction, le développement et la différenciation. Le liver receptor homolog-1 (LRH-1 ; NR5A2) est un facteur de transcription, constitutivement actif, appartenant à la famille des récepteurs nucléaires. Il est essentiellement exprimé dans les tissus d origine endodermique tels que le foie, le pancréas et l intestin. LRH-1 joue un rôle majeur dans le développement, la stéroïdogénèse et l homéostasie du cholestérol via la régulation du transport réverse du cholestérol et la biosynthèse des acides biliaires. Récemment, nous avons démontré le rôle de LRH-1 dans la régulation de la réponse de phase aiguë au niveau hépatique. En effet, la sur-expression de LRH-1dans des hépatocytes résulte en l inhibition de l induction de l expression d haptoglobine et SAA par les cytokine IL1 et IL6. De plus, l induction de la réponse inflammatoire est significativement exacerbée dans des cellules hépatiques déficientes pour LRH-1. Des études de promoteur, d ARN interférence et de chromatine immuno-précipitation révèlent que LRH-1 régule la réponse inflammatoire d une part en antagonisant la voie de signalisation C/EBP et d autre part en induisant l expression de IL-1RA ( Interleukin-1 Receptor Antagonist ). L activité anti-inflammatoire de LRH-1 est démontrée in vivo dans les souris hétérozygote pour LRH-1. LRH-1 est décrit comme régulateur du métabolisme lipidique en contrôlant l expression des gènes impliqués dans la régulation de la synthèse des acides biliaires et dans l homéostasie du cholestérol. Les particules HDL sont considérées comme des particules anti-anthérogène par leur capacité à promouvoir le transport réverse du cholestérol. Des études récentes rapporte que ApoM semble important dans la formation des particules prè -HDL et dans l efflux cholestérol induit par les particules HDL. Par ailleurs, ApoM inhibe la progression de l athérosclérose dans les souris LDLr KO. Nous avons étudié le rôle de LRH-1 dans la régulation du gène codant ApoM. En utilisant des hépatocytes déficient pour LRH-1 ou sur exprimant LRH-1, nous avons démontré que LRH-1 régule l expression de ApoM en se liant à un LRH-1 RE localisé dans le promoteur du gène. Nous démontrons également que le répresseur transcriptionnelle SHP inhibe l expression de ApoM en inhibant l activité transcriptionnelle de LRH-1 in vitro et in vivo. Les propriétés anti-inflammatoires de LRH-1 et son rôle dans l homéostasie du cholestérol sont confirmés par la caractérisation des souris LRH-1 conditionnelles KO. L ensemble de ces résultats démontre que LRH-1 est un régulateur physiologique de la réponse de phase aiguë et joue un rôle majeur dans le métabolisme du HDL-cholestèrol.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Diabetes and pulmonary infection: how hyperglycaemia shapes the immune system

International audienc

Liver Receptor Homolog 1 Is a Negative Regulator of the Hepatic Acute-Phase Response

The orphan nuclear receptor liver receptor homolog 1 (LRH-1) has been reported to play an important role in bile acid biosynthesis and reverse cholesterol transport. Here, we show that LRH-1 is a key player in the control of the hepatic acute-phase response. Ectopic expression of LRH-1 with adenovirus resulted in strong inhibition of both interleukin-6 (IL-6)- and IL-1β-stimulated haptoglobin, serum amyloid A, and fibrinogen β gene expression in hepatocytes. Furthermore, induction of the hepatic inflammatory response was significantly exacerbated in HepG2 cells expressing short hairpin RNA targeting LRH-1 expression. Moreover, transient-transfection experiments and electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that LRH-1 regulates this cytokine-elicited inflammatory response by, at least in part, antagonizing the CCAAT/enhancer binding protein β signaling pathway. Finally, we show, by using LRH-1 heterozygous mice, that LRH-1 is involved in the control of the inflammatory response at the hepatic level in vivo. Taken together, our results outline an unexpected role for LRH-1 in the modulation of the hepatic acute-phase response