Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes

Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1β (IL-1β) expression in the uterus and the placenta along with elevated circulating IL-1β concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1β antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1β antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1β is a causal driver of impaired glucose tolerance in GDM

Une nouvelle mission pour l’IL-33

International audienceNo abstract availabl

Inflammation du tissu adipeux chez le sujet obèse et au cours de la perte de poids : nouveau dialogue paracrine entre macrophages et lymphocytes

Obesity is a chronic low-grade inflammatory condition, with increased inflammatory mediators in the circulation and adipose tissue. Following up obese subjects before and after bariatric surgery, we observed a biphasic regulation of pro-inflammatory factors in circulation, showing drastic decreases at month 3 post-surgery followed by a rebound and stabilization after 1 year. Patient's nutritional status was a major determinant of this unexpected profile. In obese subjects, we found enrichment in "non-classical" CD14dimCD16+ circulating monocytes that was reduced after bariatric surgery. The pathogenicity of this particular subset in relation with low-grade inflammation remains to be established. Although obese adipose tissue is a site of immune cell infiltration in obesity, little is known about cross-talk between these cell types. We show that adipose tissue macrophages secrete IL-1β through NLRP3 inflammasome activation. This process was down-regulated by weight loss but overactivated in type 2 diabetic (T2D) patients. We also showed that the adipose tissue of obese T2D subjects is enriched in IL-17+IFN-β+ double producer lymphocytes. In primary cell co-culture experiments, adipose tissue macrophage-derived IL-1β enhanced IL-17 production by adipose tissue lymphocytes, while IL-17 reciprocally induced IL-1β secretion. T2D might exacerbate this cross-talk, as suggested by overexpression of each cytokine cognate receptor on their respective target cell. This identified IL-1β and IL-17 as two key cytokines mediating a new inflammatory cross-talk between adipose tissue macrophages and lymphocytes that might contribute to the deterioration of glycemic status in human obesityL'obésité est un état inflammatoire chronique dit de " bas grade ", associé à l'augmentation de facteurs pro-inflammatoires dans la circulation et le tissu adipeux. Chez les sujets obèses, nous montrons qu'une série de facteurs inflammatoires sériques évoluent selon une régulation bi-phasique au cours de la perte de poids induite par chirurgie bariatrique, avec une diminution drastique à 3 mois suivie d'un rebond et d'une stabilisation à 1 an. Le statut nutritionnel des patients est un déterminant majeur de ce profile inattendu. Chez ces sujets, nous mettons en évidence un enrichissement en monocytes circulants " non classiques " CD14dimCD16+, dont l'abondance diminue après perte de poids. La relevance clinique de ces observations reste à explorer. Le tissu adipeux est un site d'accumulation de cellules immunitaires dans l'obésité, mais les voies de communication entre ces cellules sont mal connues. Nous montrons que les macrophages du tissu adipeux sécrètent de l'IL-1β en réponse à l'activation de l'inflammasome NLRP3. Ce processus est augmenté chez les patients obèses diabétiques (T2D) et atténué après perte de poids. Par ailleurs, nous montrons que le tissu adipeux des patients T2D est enrichi en une population de lymphocytes produisant à la fois de l'IL-17+ et de l'IFN-β+. Dans un système de co-culture, l'IL-1β produite par les macrophages du tissu adipeux stimulent la production d'IL17 par les lymphocytes, et réciproquement. Ces résultats suggèrent que IL-1β et IL-17 sont deux cytokines clés à la base d'un dialogue paracrine et pro-inflammatoire entre macrophages et lymphocytes du tissu adipeux, spécifiquement augmenté chez les patients obèses diabétiques

Inflammation du tissu adipeux chez le sujet obèse et au cours de la perte de poids (nouveau dialogue paracrine entre macrophages et lymphocytes)

Obesity is a chronic low-grade inflammatory condition, with increased inflammatory mediators in the circulation and adipose tissue. Following up obese subjects before and after bariatric surgery, we observed a biphasic regulation of pro-inflammatory factors in circulation, showing drastic decreases at month 3 post-surgery followed by a rebound and stabilization after 1 year. Patient s nutritional status was a major determinant of this unexpected profile. In obese subjects, we found enrichment in non-classical CD14dimCD16+ circulating monocytes that was reduced after bariatric surgery. The pathogenicity of this particular subset in relation with low-grade inflammation remains to be established. Although obese adipose tissue is a site of immune cell infiltration in obesity, little is known about cross-talk between these cell types. We show that adipose tissue macrophages secrete IL-1b through NLRP3 inflammasome activation. This process was down-regulated by weight loss but overactivated in type 2 diabetic (T2D) patients. We also showed that the adipose tissue of obese T2D subjects is enriched in IL-17+IFN- + double producer lymphocytes. In primary cell co-culture experiments, adipose tissue macrophage-derived IL-1 enhanced IL-17 production by adipose tissue lymphocytes, while IL-17 reciprocally induced IL-1b secretion. T2D might exacerbate this cross-talk, as suggested by overexpression of each cytokine cognate receptor on their respective target cell. This identified IL-1 and IL-17 as two key cytokines mediating a new inflammatory cross-talk between adipose tissue macrophages and lymphocytes that might contribute to the deterioration of glycemic status in human obesityL obésité est un état inflammatoire chronique dit de bas grade , associé à l augmentation de facteurs pro-inflammatoires dans la circulation et le tissu adipeux. Chez les sujets obèses, nous montrons qu une série de facteurs inflammatoires sériques évoluent selon une régulation bi-phasique au cours de la perte de poids induite par chirurgie bariatrique, avec une diminution drastique à 3 mois suivie d un rebond et d une stabilisation à 1 an. Le statut nutritionnel des patients est un déterminant majeur de ce profile inattendu. Chez ces sujets, nous mettons en évidence un enrichissement en monocytes circulants non classiques CD14dimCD16+, dont l abondance diminue après perte de poids. La relevance clinique de ces observations reste à explorer. Le tissu adipeux est un site d accumulation de cellules immunitaires dans l obésité, mais les voies de communication entre ces cellules sont mal connues. Nous montrons que les macrophages du tissu adipeux sécrètent de l IL-1 en réponse à l activation de l inflammasome NLRP3. Ce processus est augmenté chez les patients obèses diabétiques (T2D) et atténué après perte de poids. Par ailleurs, nous montrons que le tissu adipeux des patients T2D est enrichi en une population de lymphocytes produisant à la fois de l IL-17+ et de l IFN- +. Dans un système de co-culture, l IL-1 produite par les macrophages du tissu adipeux stimulent la production d IL17 par les lymphocytes, et réciproquement. Ces résultats suggèrent que IL-1 et IL-17 sont deux cytokines clés à la base d un dialogue paracrine et pro-inflammatoire entre macrophages et lymphocytes du tissu adipeux, spécifiquement augmenté chez les patients obèses diabétiquesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

International audienceType-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis

P278 Un régime enrichi en isomères conjugués de l’acide linoléique (CLA) induit une inflammation massive et réversible du tissu adipeux chez la souris

Chez la souris, un régime enrichi en isomères conjugués de l’acide linoléique (CLA) provoque une lipodystrophie majeure. Une étude récente (Poirier et al., Diabetes, 2006, 55 : 1634) révèle l’accumulation rapide de macrophages dans le tissu adipeux blanc de souris traitées par l’isomère actif, t10, c12-CLA, après 7 jours de gavage. Nous avons utilisé ce modèle pour caractériser la cinétique d’infiltration du tissu adipeux par les différents types de cellules de l’immunité innée et adaptative

A role for interleukin-22 in the alleviation of metabolic syndrome

Increasing evidence points to a role for the immune system in the regulation of metabolism. Two new studies in mice indicate treatment with interleukin-22 restores mucosal immunity in diabetes and alleviates metabolic disease, resulting in improved glycemic control

Adipose tissue adaptive response to trans-10,cis-12-conjugated linoleic acid engages alternatively activated M2 macrophages

In mice, nutritional supplementation with the trans-10,cis-12 isomer of linoleic acid (t10,c12-CLA) promotes lipoatrophy, hyperinsulinemia, and macrophage infiltration in white adipose tissue (WAT). We explored the dynamics of these interrelated responses over 2 consecutive 7 d periods of t10,c12-CLA administration and withdrawal. t10,c12-CLA down-regulated lipogenic and lipolytic gene expression and increased collagen deposition, but with no evidence of cross-linking. An abundant CD45(+) cell infiltrate, comprising prominently CD206(+)CD11c(-) macrophages, was found in WAT in association with an anti-inflammatory gene signature. Infiltration of natural killer (NK) and dendritic cells contributed to WAT's innate immune response to t10,c12-CLA. Less abundant adaptive immune cells colonized WAT, including B, NK T, γδ T, and αβ T cells. By contrast, T-regulatory cell abundance was not affected. Interruption of treatment allowed recovery of WAT mass and normalization of insulinemia, coincident with regain of WAT homeostasis owing to a coordinated reversion of genic, structural, and immune deregulations. These data revealed a striking resilience of WAT after a short-term metabolic injury induced by t10,c12-CLA, which relies on alternatively activated M2 macrophage engagement. In addition, the temporal links between variations in WAT alterations and insulinemia upon t10,c12-CLA manipulation strengthen the view that WAT dysfunctional status is critically involved in altered glucose homeostasis.-Pini, M., Touch, S., Poirier, H., Dalmas, E., Niot, I., Rouault, C., Druart, C., Delzenne, N., Clément, K., André, S., Guerre-Millo, M. Adipose tissue adaptive response to trans-10,cis-12-conjugated linoleic acid engages alternatively activated M2 macrophages