Oleate but not stearate induces the regulatory phenotype of myeloid suppressor cells

Tumor infiltrating myeloid cells play contradictory roles in the tumor development. Dendritic cells and classical activated macrophages support anti- tumor immune activity via antigen presentation and induction of pro- inflammatory immune responses. Myeloid suppressor cells (MSCs), for instance myeloid derived suppressor cells (MDSCs) or tumor associated macrophages play a critical role in tumor growth. Here, treatment with sodium oleate, an unsaturated fatty acid, induced a regulatory phenotype in the myeloid suppressor cell line MSC-2 and resulted in an increased suppression of activated T cells, paralleled by increased intracellular lipid droplets formation. Furthermore, sodium oleate potentiated nitric oxide (NO) production in MSC-2, thereby increasing their suppressive capacity. In primary polarized bone marrow cells, sodium oleate (C18:1) and linoleate (C18:2), but not stearate (C18:0) were identified as potent FFA to induce a regulatory phenotype. This effect was abrogated in MSC-2 as well as primary cells by specific inhibition of droplets formation while the inhibition of de novo FFA synthesis proved ineffective, suggesting a critical role for exogenous FFA in the functional induction of MSCs. Taken together our data introduce a new unsaturated fatty acid-dependent pathway shaping the functional phenotype of MSCs, facilitating the tumor escape from the immune system

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+)Gr-1(+) MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/-)) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases

Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma

Background: Suppressive immune cells present in tumour microenvironments are known to augment tumour growth and hamper efficacy of antitumour therapies. The amino-bisphosphonate Zoledronic acid (ZA) is considered as an antitumour agent, as recent studies showed that ZA prolongs disease-free survival in cancer patients. The exact mechanism is a topic of debate; it has been suggested that ZA targets tumour-associated macrophages (TAMs). Methods: We investigate the role of ZA on the myeloid differentiation to TAMs in murine mesothelioma in vivo and in vitro. Mice were intraperitoneally inoculated with a lethal dose of mesothelioma tumour cells and treated with ZA to determine the effects on myeloid differentiation and survival. Results: We show that ZA impaired myeloid differentiation. Inhibition of myeloid differentiation led to a reduction in TAMs, but

Adaptable Symbol Table Management by Meta Modeling and Generation of Symbol Table Infrastructures

Many textual software languages share common concepts such as defining and referencing elements, hierarchical structures constraining the visibility of names, and allowing for identical names for different element kinds. Symbol tables are useful to handle those reference and visibility concepts. However, developing a symbol table can be a tedious task that leads to an additional effort for the language engineer. This paper presents a symbol table meta model usable to define languagespecific symbol tables. Furthermore, we integrate this symbol table meta model with a meta model of a grammar-based language definition. This enables the language engineer to switch between the model structure and the symbol table as needed. Finally, based on a grammarannotation mechanism, our approach is able to generate a symbol table infrastructure that can be used as is or serve as a basis for custom symbol tables.Comment: 8 pages, 9 figures, Domain-Specific Modeling Workshop 2015 (DSM 2015

„Antibiotic-stewardship“(ABS)-Strategien in der urologischen Praxis und Klinik

Antibiotics are effective and safe drugs which have saved millions of lives since their inception. The World Health organization (WHO) has identified increasing antibiotic resistance worldwide as one of the greatest health problems of our time. The most common indications for antibiotic therapy include urinary tract infections, but according to current data, a very high percentage of these are not treated in accordance with guidelines. To prevent the continuous selection of resistant bacteria, and undesirable or even dangerous side effects such as by avoiding damage to the patient's microbiome, strategies through antibiotic stewardship (ABS) are urgently needed. Especially for urologists in outpatient care, this requires new, innovative and sustainable training concepts that keep knowledge continuously up-to-date and support appropriate antibiotic prescriptions

„Antibiotic-stewardship“(ABS)-Strategien in der urologischen Praxis und Klinik

ZusammenfassungAntibiotika sind wirksame und sichere Arzneimittel und haben seit ihrer Einführung Millionen von Menschenleben gerettet. Die Weltgesundheitsorganisation (WHO) hat die weltweit zunehmenden Antibiotikaresistenzen als eines der größten Gesundheitsprobleme der Gegenwart identifiziert. Zu den häufigsten Indikationen für eine Antibiotikatherapie gehören Harnwegsinfektionen, bei denen nach aktuellen Erfassungen in einem sehr hohen Prozentsatz allerdings nicht leitliniengerecht behandelt wird. Um die fortlaufende Selektion von resistenten Bakterien, und unerwünschte oder sogar gefährliche Nebenwirkungen wie z. B. durch Schädigungen des Mikrobioms der Patienten zu vermeiden, sind dringend Strategien zur Verbesserung der Antibiotikatherapie durch „antibiotic stewardship“ (ABS) erforderlich. Insbesondere für Urologen in der ambulanten Patientenversorgung bedarf es hierfür neuer, innovativer und nachhaltiger Schulungskonzepte, die Wissen kontinuierlich aktuell halten und sachgerechte Antibiotikaverschreibungen nachhaltig unterstützen.</jats:p

Deciphering the mechanisms of action underlying probiotic properties of Shouchella clausii by a functional genomics approach

Abstract Probiotics are widely used for their health promoting effects, though a lot remain to be discovered, particularly on their mechanisms of action at the molecular level. The functional genomic approach is an appropriate method to decipher how probiotics may influence human cell fate and therefore contribute to their health benefit. In the present work, we focused on Shouchella clausii (formerly named Bacillus then Alkalihalobacillus clausii), a spore-forming bacterium that is commercially available as a probiotic for the prevention and the treatment of intestinal dysbiosis and related gastrointestinal disorders, such as diarrhoea. Several studies have demonstrated that S. clausii treatment modulated inflammatory and immune responses, as well as gut barrier functions. A functional genomic strategy was implemented to decipher the mechanisms by which S. clausii exerts its probiotic effects on human intestinal epithelial cells. To do so, a large genomic DNA fragment library was constructed for each of the four strains: O/C, N/R, SIN and T. A high throughput in vitro screening in human epithelial cells was then conducted, using the reporter gene strategy, targeting the nuclear factor kappa B (NF-κB) pathway and interleukin-10 (IL-10) gene expression. After an exhaustive in vitro screening of approximately a thousand clones per library, several clones modulating the NF-κB pathway in the HT-29 reporter cell line were identified. Among clone lysates, 1.1% (O/C), 1.4% (N/R), 2.0% (SIN), and 1.2% (T) were identified as biologically active on immune reporter systems (NF-κB and IL-10 expression). After transposon mutagenesis and a new set of screening and sequencing, 23 coding sequences (CDS) were identified, including one encoding for the glutamine synthetase, associated with NF-κB modulation, and six CDS for IL-10 modulation. The functional genomic strategy that was applied to S. clausii was an original approach to identify gene candidates that may explain the mechanisms of action of probiotics. However, further work is needed to validate the identified leads.</jats:p