Regulation of T lymphocytes by adipose stem cells : impact on chronic inflammation and insulinresistance in obese adipose tissue

En condition d'obésité, le tissu adipeux est le théâtre d'infiltration et d'accumulation de cellules immunitaires dont les lymphocytes Th17, impliqués dans de nombreuses maladies inflammatoires chroniques et auto-immunes. Les mécanismes d'activation et de prolifération des Th17 au sein du tissu adipeux ne sont pas connus. Nous avons suggéré un rôle des cellules souches adipocytaires (CSA) dans l'induction de l'inflammation médiée par les Th17. Nos résultats montrent, pour la première fois, et grâce à un modèle de co-culture combinant les CSA du tissu adipeux obèse avec des cellules mononucléées du sang circulant, que seules les CSA issues de sujets obèses, et non pas de sujets minces, sont capables d'induire l'activation des Th17 et des monocytes, qui en retour activent la sécrétion d'IL-6 par les CSA. L'environnement inflammatoire, induit par cette interaction, est à l'origine de l'inhibition de l'adipogenèse et de la réduction de la sensibilité à l'insuline des adipocytes. De plus, tout comme les CSA, les adipocytes issus de sujets obèses induisent le même phénotype inflammatoire. Enfin, une étude en cours nous a permis de montrer que les acides gras polyinsaturés de type -3, inhibent spécifiquement l'activation des Th17 mais n'ont aucun impact sur les monocytes inflammatoires, dans notre modèle, possiblement lié à une inhibition de l'expression d'ICAM-1. En conclusion, une triade inflammatoire constituée de CSA ou d'adipocytes issus de sujets obèses combinés avec des monocytes et des Th17, forme un cercle vicieux où l'inflammation est maintenue et amplifiéeIn obesity, adipose tissue is massively infiltrated by a panel of inflammatory immune cells such as IL-17-secreting Th17 lymphocytes. The mechanisms by which Th17 cells are induced are less understood. We postulated that adipose stem cells (ASC), which are known to play immunomodulatory functions in contact with immune cells, might be involved in Th17 activation. By using an in-vitro co-culture model, we demonstrated for the first time, that ASC issued from obese , but not lean AT were able to activate IL-17 secretion from Th17 cells, and IL-1 secretion from monocytes. In turn, such an interaction led to increased secretion of IL-6 from ASC. The inflammatory environment generated from this interaction was then able to inhibit adipogenesis and adipocyte insulin-sensitivity. We also showed that adipocytes harvested from obese adipose tissue were able to promote Th17 cell and monocyte activation. Finally, we demonstrated that polyunsaturated fatty acids omega-3 presented anti-inflammatory properties towards Th17 cells, while they had no effect on monocytes in our co-culture model (manuscript in preparation), which was related to decrease of ICAM-1 expression. In conclusion, we highlight herein a crosstalk between ASC, monocytes and Th17 cells in obese adipose tissue, which leads to a vicious circle of pro-inflammatory cytokine secretio

Régulations fonctionnelles des lymphocytes T par les cellules souches adipocytaires : implication dans l’inflammation chronique et l’insulinorésistance du tissu adipeux du sujet obèse

In obesity, adipose tissue is massively infiltrated by a panel of inflammatory immune cells such as IL-17-secreting Th17 lymphocytes. The mechanisms by which Th17 cells are induced are less understood. We postulated that adipose stem cells (ASC), which are known to play immunomodulatory functions in contact with immune cells, might be involved in Th17 activation. By using an in-vitro co-culture model, we demonstrated for the first time, that ASC issued from obese , but not lean AT were able to activate IL-17 secretion from Th17 cells, and IL-1 secretion from monocytes. In turn, such an interaction led to increased secretion of IL-6 from ASC. The inflammatory environment generated from this interaction was then able to inhibit adipogenesis and adipocyte insulin-sensitivity. We also showed that adipocytes harvested from obese adipose tissue were able to promote Th17 cell and monocyte activation. Finally, we demonstrated that polyunsaturated fatty acids omega-3 presented anti-inflammatory properties towards Th17 cells, while they had no effect on monocytes in our co-culture model (manuscript in preparation), which was related to decrease of ICAM-1 expression. In conclusion, we highlight herein a crosstalk between ASC, monocytes and Th17 cells in obese adipose tissue, which leads to a vicious circle of pro-inflammatory cytokine secretionEn condition d'obésité, le tissu adipeux est le théâtre d'infiltration et d'accumulation de cellules immunitaires dont les lymphocytes Th17, impliqués dans de nombreuses maladies inflammatoires chroniques et auto-immunes. Les mécanismes d'activation et de prolifération des Th17 au sein du tissu adipeux ne sont pas connus. Nous avons suggéré un rôle des cellules souches adipocytaires (CSA) dans l'induction de l'inflammation médiée par les Th17. Nos résultats montrent, pour la première fois, et grâce à un modèle de co-culture combinant les CSA du tissu adipeux obèse avec des cellules mononucléées du sang circulant, que seules les CSA issues de sujets obèses, et non pas de sujets minces, sont capables d'induire l'activation des Th17 et des monocytes, qui en retour activent la sécrétion d'IL-6 par les CSA. L'environnement inflammatoire, induit par cette interaction, est à l'origine de l'inhibition de l'adipogenèse et de la réduction de la sensibilité à l'insuline des adipocytes. De plus, tout comme les CSA, les adipocytes issus de sujets obèses induisent le même phénotype inflammatoire. Enfin, une étude en cours nous a permis de montrer que les acides gras polyinsaturés de type -3, inhibent spécifiquement l'activation des Th17 mais n'ont aucun impact sur les monocytes inflammatoires, dans notre modèle, possiblement lié à une inhibition de l'expression d'ICAM-1. En conclusion, une triade inflammatoire constituée de CSA ou d'adipocytes issus de sujets obèses combinés avec des monocytes et des Th17, forme un cercle vicieux où l'inflammation est maintenue et amplifié

Beneficial Effects of Fasting on White Adipose Tissue Inflammation and Metabolic Syndrome in Obese Subjects: Review

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Pathogenic Role of IL-17-Producing Immune Cells in Obesity, and Related Inflammatory Diseases

International audienceObesity is associated with low-grade chronic inflammation. Indeed, adipose tissues (AT) in obese individuals are the former site of progressive infiltration by pro-inflammatory immune cells, which together with increased inflammatory adipokine secretion induce adipocyte insulin resistance. IL-17-producing T (Th17) cells are part of obese AT infiltrating cells, and are likely to be promoted by adipose tissue-derived mesenchymal stem cells, as previously reported by our team. Whereas Th17 cell are physiologically implicated in the neutralization of fungal and bacterial pathogens through activation of neutrophils, they may also play a pivotal role in the onset and/or progression of chronic inflammatory diseases, or cancer, in which obesity is recognized as a risk factor. In this review, we will highlight the pathogenic role of IL-17A producing cells in the mechanisms leading to inflammation in obesity and to progression of obesity-related inflammatory diseases

Contribution of adipose stem cells from obese subjects to hepato-or breast-carcinoma tumorogenesis, through promotion of Th17 cells

Introduction:As opposed with lean adipose tissues (AT), obese AT are heavily infiltrated with variety of inflammatory cells. Among them, Th17 cells are found not only within AT, but also in the periphery in obese subjects. We have demonstrated that AT-derived stem cells (ASC), or their progenitors, contribute to inflammation through promotion of Th-17 cells, provided that they are issued from obese-, but not lean-AT (Diabetes, 2015; Adipocyte, 2016). Because obesity is associated with increased prevalence of various cancers, including hepatic or breast cancer, we postulated herein that ASC-mediated promotion of Th17 cells might result in tumorogenesis progression.Materials and Methods:Human ASC were isolated from WAT of obese donors (obASC). Mononuclear cells (MNC) were collected from blood donors. PHA-activated co-cultures of obASC/MNC, which increase secretion of IL-17A, IL--6, were performed. Conditioned media (CM) were collected from such cultures, and added to HuH7 (hepato-carcinoma cell line) or MCF-7 / MDA-MB-231 (breast carcinoma cell line) cultures for 24h. mRNA profiles were measured by qRT-PCR. Expression of CXCR4 was measured by flow cytometry.Results:CM from 48 hr PHA-activated-ASC/MNC co-cultures enhanced IL--8 TNF-IL-6 mRNA expression in HUH7 by almost 700, 2, 3, 3, and 6-fold, respectively. A putative effect of CM on HUH7 invasiveness was supported by 2a –fold, and 3-fold increase in MMP9, and CXCR4 expression, respectively. In addition, CM also increased IL--6, IL-8 and VEGF-in both MCF-7 and MDA-MB-231 cell lines.Conclusion:Our results suggest that the interaction of ob ASC with immune cells contribute to an inflammatory environment, able to impact hepato- or breast-carcinoma cell secretion profile, and/or invasiveness, either through propagation of inflammatory cytokines outside adipose tissues, or ASC migration inside tumor

IL-17A contributes to propagation of inflammation but does not impair adipogenesis and/or insulin response, in adipose tissue of obese individuals

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Adipocytes, like their progenitors, contribute to inflammation of adipose tissues through promotion of Th-17 cells and activation of monocytes, in obese subjects

Recently, we have reported that adipose tissue-derived stem cells (ASC) harvested from obese donors induce a pro-inflammatory environment when co-cultured with peripheral blood mononuclear cells (MNC), with a polarization of T cells toward the Th17 cell lineage, increased secretion of IL-1 and IL-6 pro-inflammatory cytokines, and down-regulation of Th1 cytokines, such as IFN and TNF. However, whether differentiated adipocytes, like the aforementioned ASC, are pro-inflammatory in obese subject AT remained to be investigated. Herein, we isolated ASC from AT of obese donors and differentiated them into adipocytes, for either 8 or 14d. We analyzed their capacity to activate blood MNC after stimulation with phytohemagglutinin A (PHA), or not, in co-culture assays. Our results showed that co-cultures of MNC with adipocytes, like with ASC, increased IL-17A, IL-1, and IL-6 pro-inflammatory cytokine secretion. Moreover, like ASC, adipocytes down-regulated TNF secretion by Th1 cells. As adipocytes differentiated from ASC of lean donors also promoted IL-17A secretion by MNC, an experimental model of high-fat versus chow diet mice was used and supported that adipocytes from obese, but not lean AT, are able to mediate IL-17A secretion by PHA-activated MNCs. In conclusion, our results suggest that, as ASC, adipocytes in obese AT might contribute to the establishment of a low-grade chronic inflammation state

Contribution of obese adipose tissue-derived stem cells to hepato-or breast-carcinoma inflammation, through promotion of Th17 cells and activation of IL-1b by monocytes

Background and aims:As opposed with lean adipose tissues (AT), obese AT are heavily infiltrated with variety of inflammatory cells such as macrophages and Th17 cells. Obesity-mediated chronic low-grade inflammation is known to contribute to tumor progression in various cancers, including hepatic and breast cancers. Because we have previous-ly demonstrated, using co-culture experiments, that obese AT-derived stem cells (obASC) contribute to AT inflammation through promotion of Th17 cells, and activation of IL-1β-secreting monocytes, we postulated herein that such inflammatory environment could contribute to tumor progression in cancer-suffering obese patients.Materials and methods:Human ASC were isolated from AT of obese donors. Mononuclear cells (MNC) were collected from healthy blood donors. Co-cultures of obASC and MNC were activated for 48 hours with phytohemagglutinin A ( PHA), a T cell mitogen, or not. Conditionned media (CM) were collected, and added for 24h to cultures of HuH7 (hepatocarinoma cell line) or of two breast carcinoma cell lines, i.e MCF-7, or MDA-MB-231. Levels of inflammatory or angiogenic gene expression were evaluated by qRT-PCR. Expression of CXCR4 (a marker of invasiveness) was measured by flow cytometry in the HuH7 cell line.Results:CM from PHA-activated-obASC/MNC co-cultures enhanced IL-1 β ,IL-8andVEGF α mRNA expression in HuH7 cells by 1942.2, 45.7 and 6.1 -fold, respectively, as compared with no treatment. A putative effect of CM on HuH7 invasiveness was supported by a 2- and 3-fold increase in MMP-9, and CXCR4 expression, respectively. In addition, IL-1β, IL-8 and VEGF-α mRNA expression were increased by 34.3, 33.2, and 2.97 fold respectively in MCF-7 cells, and by 85.8, 52.0 , and 1.34 fold respectively, in MDA-MB-231 cells. These results indicated thus a differential sensitivity of cancer cell lines to CM from PHA-activated-ob ASC/MNC co-cultures, with a preponderant increase of IL-1 β mRNA levels in hepatocarcinoma cells versus a similar increase of IL-1β and IL-8 gene expression in breast carcinoma cells.Conclusion:Our results suggest that in cancer-suffering obese patients, interaction of obASC with AT-infiltrating immune cells contribute to the establishment of an inflammatory environment, propitious to tumor inflammation and/or tumor migration. Whether this inflammation could occur through propagation of obese AT inflammatory environment towards tumors, or through migration of ASC inside tumors and then inter-action with tumor infiltrating immune cells, remain to be explored

Adipose stem cells contribute to inflammation and insulin resistance through both TH-17 polarisation and increased pro-inflammatory cytokine secretion

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