194 research outputs found
Salt sensitivity includes effects on immune cell signalling and metabolism
No full textExcess salt (sodium chloride) intake is a risk factor for hypertension and is attributed to increasing rates of morbidity and mortality from cardiovascular diseases. Salt sensitivity is classically defined as the blood pressure response to dietary salt changes. However, in addition to the pivotal role of sodium (Na+) in regulating the osmotic composition of body fluids, we recently reported that Na+ regulates the energy metabolism of immune cells. Thus, we suggest broadening the definition of salt sensitivity to include these effects on cellular immunometabolism
The Role of High-Salt Diet on Melanoma Growth
No full textCutaneous melanoma is one of the most aggressive cancer types in Western countries with a rising incidence over the last decades. Treatment of early-diagnosed melanoma constitutes a good survival rate and recovery. However, melanoma is a multifaceted disease with high mutational burden that hinders novel therapeutic strategies. Another risk factor in developed countries is the excessive consumption of processed food, the so-called Western diet. This diet is characterized by high content of fat, sugar, proteins, and salt. It is widely believed that a high-salt diet (HSD) leads to sodium accumulation in the skin and modulates the immune system towards a pro-inflammatory state.
The main goal of the thesis was to investigate the influence of a HSD on cutaneous cancer growth and to identify cellular and molecular mechanisms for potential therapeutic strategies. Mice fed with HSD showed significantly less tumor volume compared to mice under a control diet. Furthermore, metastasis formation in the lung tissue was also reduced in mice under HSD. Analysis of the tumor microenvironment revealed a similar abundance of immune cells in both investigated groups. Furthermore, the distribution of immune cells in the tumor-draining lymph nodes was not altered by the increased salt intake so the role of the immune system was excluded in the HSD-mediated tumor reduction
Instead, HSD tremendously affects tumor metabolism by reducing glycolysis and oxidative phosphorylation activity. Transcriptomic analysis revealed downregulation of cell cycle and metabolism-associated pathways, and metabolomic profiling of tumor tissue confirmed downregulation of glycolysis and fatty acid metabolism. Analyzing glycolytic enzymes showed downregulation of mRNA levels in melanoma cells under HSD, strengthening the theory that excessive salt intake impairs glycolysis.
Furthermore, melanoma cells after HSD showed significant upregulation of modulators involved in the melanogenesis pathway. This activity may rather promote melanoma toward cell differentiation and result in the inhibition of cell proliferation.
In conclusion, the thesis revealed new insights into how HSD influences melanoma growth. The direct effect of HSD affects tumor metabolism and could be considered in future therapeutic approaches. Furthermore, the presented data indicate changes in melanogenesis activity in melanoma cells exposed to HSD and may explain the salt-mediated tumor reduction
Die unerwartete Kraft des weißen Goldes: Na+ in der Infektionsabwehr und Immunphysiologie
No full textFragen des Natriumhaushalts im Menschen beschäftigten bis vor kurzem weder Immunologen noch Infektiologen. Man ging vereinfachend davon aus, dass sich das außerhalb der Zellen befindliche, d. h. extrazelluläre Natrium im Körper gleichmäßig verteilt, so dass die Niere alleine in der Lage ist, die gesamte extrazelluläre Natriumbilanz zu regulieren. Daher glaubte man zu wissen, dass die im Blut gemessenen Natriumkonzentrationen auch die Natriumspiegel in der extrazellulären Flüssigkeit der Gewebe und Organe widerspiegeln. Diese Annahme scheint jedoch eine starke Vereinfachung darzustellen. So hat man beispielsweise herausgefunden, dass es bei natriumreichen Diäten zu einer Natriumanreicherung in der Haut kommen kann. Heute wissen wir, dass Makrophagen – Fresszellen unseres Immunsystems – in der Regulation dieses natriumreichen Mikromilieus eine wichtige, immunphysiologische Rolle spielen, indem sie den Abtransport von Natrium aus der Haut organisieren. Überraschenderweise kann es auch im Kontext von entzündlichen und infektiösen Prozessen zu einer diätunabhängigen Natriumanreicherung im Gewebe kommen, die wiederum die Aktivität und Funktionalität der Immunzellen verändert. So fördert die gesteigerte Natriumverfügbarkeit beispielsweise die Wehrhaftigkeit der Makrophagen gegenüber Infektionserregern. Die lokale Natriumbilanz stellt somit eine neue, bisher unterschätzte Stellgröße des Immunsystems dar, die Einfluss auf die Infektionsabwehr und Immunphysiologie nimmt
Virulence of broad- and narrow-host-range Salmonella enterica serovars in the streptomycin-pretreated mouse model.
No full textSalmonella enterica subspecies I serovars are common bacterial pathogens causing diseases ranging from enterocolitis to systemic infections. Some serovars are adapted to specific hosts, whereas others have a broad host range. The molecular mechanisms defining the virulence characteristics and the host range of a given S. enterica serovar are unknown. Streptomycin pretreated mice provide a surrogate host model for studying molecular aspects of the intestinal inflammation (colitis) caused by serovar Typhimurium (S. Hapfelmeier and W. D. Hardt, Trends Microbiol. 13:497-503, 2005). Here, we studied whether this animal model is also useful for studying other S. enterica subspecies I serovars. All three tested strains of the broad-host-range serovar Enteritidis (125109, 5496/98, and 832/99) caused pronounced colitis and systemic infection in streptomycin pretreated mice. Different levels of virulence were observed among three tested strains of the host-adapted serovar Dublin (SARB13, SD2229, and SD3246). Several strains of host restricted serovars were also studied. Two serovar Pullorum strains (X3543 and 449/87) caused intermediate levels of colitis. No intestinal inflammation was observed upon infection with three different serovar Paratyphi A strains (SARB42, 2804/96, and 5314/98) and one serovar Gallinarum strain (X3796). A second serovar Gallinarum strain (287/91) was highly virulent and caused severe colitis. This strain awaits future analysis. In conclusion, the streptomycin pretreated mouse model can provide an additional tool to study virulence factors (i.e., those involved in enteropathogenesis) of various S. enterica subspecies I serovars. Five of these strains (125109, 2229, 287/91, 449/87, and SARB42) are subject of Salmonella genome sequencing projects. The streptomycin pretreated mouse model may be useful for testing hypotheses derived from this genomic data
Impact of oxygen and glucose differential availability on human neutrophil viability, metabolism and activation
No full textLes neutrophiles sont les leucocytes les plus abondants dans la circulation sanguine et jouent un rôle clé dans l’immunité innée contre les agents pathogènes, en particulier les bactéries.Dans des conditions homéostatiques, les neutrophiles résident dans la moelle osseuse, où ils sont produits, et dans la fraction plasmatique du sang. Ces deux compartiments sont connus pour contenir de faibles quantités d'oxygène disponible (4 % et 1,2 % O2).En outre, les neutrophiles sont considérés comme des cellules hautement glycolytiques, ayant un faible nombre de mitochondries et produisant la majeure partie de leur énergie à partir du glucose présent dans le milieu extracellulaire. Lors d'une inflammation/infection, les neutrophiles migrent dans des tissus plus oxygénés (<10% O2), avant leur arrivée sur les sites d'inflammation, souvent décrits comme hypoxiques (<2% O2). Par conséquent, les neutrophiles présents sur les sites d'inflammation ont rencontré une disponibilité différentielle de l'oxygène.De plus, outre les variations de l'oxygène, la disponibilité d'autres métabolites fluctue également tout au long de leur migration vers les sites d'inflammation, l'un de ces métabolites étant le glucose. Bien que les neutrophiles soient considérés comme des cellules différenciées, des rapports récents ont mis en évidence la plasticité des neutrophiles pour ajuster leur métabolisme en fonction de l’environnement, de la même manière que les macrophages, qui peuvent avoir un phénotype glycolytique (M1) ou oxydatif (M2).Ces découvertes ont conduit à reconsidérer le rôle des mitochondries dans les neutrophiles, autrefois considérées comme importantes uniquement dans l'induction de la mort cellulaire (apoptose).Cependant, l'impact de la disponibilité différentielle de l'oxygène et du glucose sur l'activation des neutrophiles et le métabolisme énergétique reste encore à déterminer. Par ailleurs, le rôle des mitochondries dans l'activation des neutrophiles et les fonctions antimicrobiennes n'est pas entièrement compris.En utilisant des échantillons de côlon de cobaye infecté à la bactérie Shigella, nous avons pu établir qu'en plus de l'oxygène, le glucose est également absent dans les tissus infectés contenant un nombre élevé de neutrophiles. Grâce à des essais in vitro supplémentaires sur les neutrophiles humains périphériques, nous avons pu étudier l'impact de la disponibilité différentielle de l'oxygène et du glucose sur l'activation et les fonctions des neutrophiles.Nos résultats ont révélé qu'une exposition prolongée à l'oxygène accélère la mort et l'activation des neutrophiles.D'une part, nos découvertes ont démontré que le glucose a un impact inhibiteur direct sur la capacité de travail maximale de la fonctionnalité de la chaîne respiratoire mitochondriale des neutrophiles humains. D’autre part, la privation de glucose à court terme en cas d'anoxie a réduit le potentiel de membrane mitochondriale, restauré grâce à l'ajout de glucose, indiquant que le glucose joue un rôle important dans le maintien de la fonctionnalité des mitochondries des neutrophiles dans des environnements à faible teneur en oxygène.Avec l'analyse de l'expression génétique, les tests fonctionnels mitochondriales et les tests des capacités antimicrobiens, nous avons pu établir que la disponibilité de l'oxygène et du glucose a un impact important sur le phénotype et la fonctionnalité des neutrophiles.Neutrophils are the most abundant leukocytes in the circulation and are key players of the innate immune response against pathogens, especially bacteria. Under homeostatic conditions, neutrophils reside in the bone marrow where they are produced, circulate in the plasma fraction of the blood. Both compartments are known to contain low amounts of available oxygen (<4% and <1.2% O2 respectively). Moreover, neutrophils are considered highly glycolytic cells, having a low number of mitochondria and producing most of their energy from glucose uptake from the environment. During inflammation/infection, neutrophils migrate into more oxygenated tissues (<10%) to reach inflammatory sites, often described as hypoxic (<2% O2). Hence, neutrophils present in inflammatory sites have encountered various levels of oxygen. Moreover, besides oxygen variations, other metabolite availability also fluctuates throughout their migration into inflammation sites, one of these metabolites being glucose. Although neutrophils are considered terminally differentiated cells, recent reports have highlighted the plasticity of neutrophils to tune their metabolism according to the surrounding environment similarly to macrophages, which can have either a glycolytic (M1) or an oxidative (M2) phenotype. These discoveries have led to a reconsideration of the role of mitochondria in neutrophils, formerly considered important only for cell death (apoptosis) induction. However, how differential oxygen and glucose availability impact neutrophil activation and energy metabolism still remains elusive. Furthermore, the role of mitochondria during neutrophil activation and anti-microbial functions is not fully understood.Using our model of Shigella infection of the guinea pig’s colon we demonstrated that besides oxygen, glucose is also depleted in infected tissues, containing high numbers of neutrophils. With additional in vitro assays performed on human peripheral neutrophils, we revealed that prolonged oxygen exposure promotes neutrophil cell death and activation. On the other hand, we demonstrated that glucose has a direct inhibitory impact on the neutrophil mitochondrial electron transport chain maximal work capacity and functionality. Moreover, short-term glucose starvation in anoxia lowered the mitochondrial membrane potential, which was restored with glucose supplementation, indicating that glucose has an important role in the maintenance of the functionality of mitochondria in neutrophils in low oxygen environments. Together with gene expression analysis, mitochondrial functionality assays and anti-microbial assays, we demonstrated that the availability of both oxygen and glucose greatly impact the phenotype and functionality of neutrophils
Hypoxia and hypoxia-inducible factors in myeloid cell-driven host defense and tissue homeostasis
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Filifactor alocis and Tumor Necrosis Factor-Alpha Stimulate Synthesis of Visfatin by Human Macrophages.
No full textThere is little known about the effect of the periodontopathogen Filifactor alocis on macrophages as key cells of the innate immune defense in the periodontium. Therefore, the aim of the present study was to investigate the effect of F. alocis and additionally of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) on visfatin and other pro-inflammatory and proteolytic molecules associated with periodontitis in human macrophages. The presence of macrophage markers CD14, CD86, CD68, and CD163 was examined in gingival biopsies from healthy individuals and periodontitis patients. Human macrophages were incubated with F. alocis and TNFα for up to 2 d. The effects of both stimulants on macrophages were determined by real-time PCR, ELISA, immunocytochemistry, and immunofluorescence. F. alocis was able to significantly stimulate the synthesis of visfatin by human macrophages using TLR2 and MAPK pathways. In addition to visfatin, F. alocis was also able to increase the synthesis of cyclooxygenase 2, TNFα, and matrix metalloproteinase 1. Like F. alocis, TNFα was also able to stimulate the production of these proinflammatory and proteolytic molecules. Our results highlight the pathogenetic role of F. alocis in periodontal diseases and also underline the involvement of visfatin in the aetiopathogenesis of periodontitis
On microbial syringes : Advances in our understanding of type III secretion systems in bacterial pathogenesis: Comment on “An elegant nano-injection machinery for sabotaging the host : Role of Type III secretion system in virulence of different human and animal pathogenic bacteria” by Dipshika Chakravortty et al
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