TGFbeta Family Members Are Key Mediators in the Induction of Myofibroblast Phenotype of Human Adipose Tissue Progenitor Cells by Macrophages

International audienceOBJECTIVE: The present study was undertaken to characterize the remodeling phenotype of human adipose tissue (AT) macrophages (ATM) and to analyze their paracrine effects on AT progenitor cells. RESEARCH DESIGN AND METHODS: The phenotype of ATM, immunoselected from subcutaneous (Sc) AT originating from subjects with wide range of body mass index and from paired biopsies of Sc and omental (Om) AT from obese subjects, was studied by gene expression analysis in the native and activated states. The paracrine effects of ScATM on the phenotype of human ScAT progenitor cells (CD34(+)CD31(-)) were investigated. RESULTS: Two main ATM phenotypes were distinguished based on gene expression profiles. For ScAT-derived ATM, obesity and adipocyte-derived factors favored a pro-fibrotic/remodeling phenotype whereas the OmAT location and hypoxic culture conditions favored a pro-angiogenic phenotype. Treatment of native human ScAT progenitor cells with ScATM-conditioned media induced the appearance of myofibroblast-like cells as shown by expression of both α-SMA and the transcription factor SNAIL, an effect mimicked by TGFβ1 and activinA. Immunohistochemical analyses showed the presence of double positive α-SMA and CD34 cells in the stroma of human ScAT. Moreover, the mRNA levels of SNAIL and SLUG in ScAT progenitor cells were higher in obese compared with lean subjects. CONCLUSIONS: Human ATM exhibit distinct pro-angiogenic and matrix remodeling/fibrotic phenotypes according to the adiposity and the location of AT, that may be related to AT microenvironment including hypoxia and adipokines. Moreover, human ScAT progenitor cells have been identified as target cells for ScATM-derived TGFβ and as a potential source of fibrosis through their induction of myofibroblast-like cells

CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies

BACKGROUND: Adipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L--an established marker and mediator of cardiovascular disease--induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo. METHODOLOGY/PRINCIPAL FINDINGS: WT or CD40L(-/-) mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L(-/-) mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L(-/-) mice. However, CD40L(-/-) mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L(-/-) mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels. CONCLUSION: We present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease

Autoimmunity to HSP60 during diet induced obesity in mice

Adaptive immunity has been implicated in adipose tissue inflammation, obesity and its adverse metabolic consequences. No obesity-related autoantigen has yet been identified, although heat shock protein 60 (HSP60) has been implicated in other autoimmune diseases. We investigated whether feeding a high-fat diet to C57BL/6J mice would cause autoimmunity to HSP60 and whether immunomodulation with peptides from HSP60 would reverse the resulting obesity or metabolic dysfunction. Obese mice had higher circulating levels of HSP60 associated with increased T-lymphocyte proliferation responses and the emergence of circulating IgG1 and IgG2c antibody levels against HSP60. Treatment with escalating doses of a mixture of three proven immunomodulatory HSP60 peptides did not reduce weight but completely reversed the increase in VLDL/LDL levels and partially reversed the glucose intolerance in obese mice. Obese mice mount an autoimmune response to HSP60, which partly underlies the resulting metabolic disturbances

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

The Immune System in Stroke

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches

Estado de ánimo y de salud del personal universitario durante el periodo de aislamiento por COVID-19

Aims: The objective of this research was to know the state of mind and health of the personnel working in the Universities of the Cuenca-Ecuador canton, during the period of isolation due to the COVID-19 pandemic. Materials and methods: This were a quantitative, descriptive and cross-sectional research, carried out in the universities of the province of Azuay, after obtaining the permission of the Bioethics Committee, a validated survey was applied, whose independent variable was mood in the staff of the four universities in the process of isolation by COVID-19, the data 610 data were analyzed using the SPSS statistical program. Results: The number of resulting electronic surveys was 610. We found data of affection in the mood of the employees, especially in groups of young employees between 18 and 44 years old (p=0.002), with reference to sex, women present greater wear and tear in their mood with 66.56% over men 59.17% (p= 0.047). In addition to this, 65.02% did not present pathologies and the remaining percentage of workers showed diseases of various etiologies. Conclusions: University employees presented a deterioration in their mood, as an effect of the health crisis we are going through worldwide and presented a low prevalence of other pre-existing diseases in this period of isolation, among which the most frequent were those associated with metabolic damage.Objetivo: El objeto de esta investigación fue conocer el estado de ánimo y de salud del personal que labora en las Universidades del cantón Cuenca-Ecuador, en el periodo de aislamiento por la pandemia COVID-19. Materiales y métodos: Se trató de una investigación de tipo cuantitativo, descriptivo y transversal, realizada en las Universidades de la provincia del Azuay, previa obtención del permiso de Comité de Bioética se aplicó una encuesta validada, cuya variable independiente fue estado de ánimo en los funcionarios de las cuatro universidades en el proceso de aislamiento por covid-19, los datos 610 datos fueron analizados mediante el programa estadístico SPSS. Resultados: El número de encuestas electrónicas resultantes fue 610. Se encontraron datos de afección en el estado de ánimo de los funcionarios especialmente en grupos de funcionarios jóvenes de 18 a 44 años (p=0,002), con referencia al sexo las mujeres presentan mayor desgaste en su estado anímico con un 66,56% sobre los varones 59,17% (p= 0,047). Adicional a esto, el 65,02% no presentan patologías y el porcentaje restante de trabajadores mostró enfermedades de diversas etiologías. Conclusiones: Los funcionarios universitarios presentaron un deterioro en su estado de ánimo, como efecto de la crisis sanitaria que atravesamos a nivel mundial y presentaron una baja prevalencia de otras enfermedades preexistentes en este periodo de aislamiento, entre las cuales las más frecuentes fueron las que se asocian a daños metabólicos

Giant paleo-seafloor craters and mass wasting associated with magma-induced uplift of the upper crust

Giant seafloor craters are known along many a continental margin with recurrent mass-wasting deposits. However, the impact of breakup-related magmatism on the evolution of such craters is barely understood. Using high-quality geophysical datasets, this work examines the genetic relationship among the location of magmatic sills, forced folds and the formation of giant paleo-seafloor craters underneath an ancient mass-transport complex in the Møre and Vøring basins, offshore Norway. The data reveal that forced folding of near-seafloor strata occurred because of the intrusion of several interconnected magmatic sills. Estimates of 1-dimensional uplift based on well data show that uplift occurred due to the intrusion of magma in Upper Cretaceous to Lower Eocene strata. Our findings also prove that subsurface fluid plumbing associated with the magmatic sills was prolonged in time and led to the development of several vertical fluid flow conduits, some of which triggered mass wasting in Neogene to Recent times. The repeated vertical expulsion of subsurface fluids weakened the strata on the continental slope, thereby promoting mass wasting, the selective cannibalization of the paleo-seafloor, and the formation of elongated craters at the basal shear zone of the mass-transport complex. Significantly, the model presented here proves a close link between subsurface magmatic plumbing systems and mass wasting on continental margins.</p