Hydrogen-Peroxide Synthesis and LDL-Uptake Controls Immunosuppressive Properties in Monocyte-Derived Dendritic Cells

Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H2O2) depletion. However, the effects on monocyte-derived dendritic cells (moDCs) are unknown. Methods: Monocytes from healthy donors were differentiated to moDCs in the presence of extracellular enzymatic H2O2-depletion (hereinafter CAT-DCs), and studied phenotypically and functionally. To elucidate the underlying molecular mechanisms, we analyzed H2O2- and LDL-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: CAT-DCs were of an immature DC phenotype, particularly characterized by impaired expression of the costimulatory molecules CD80/86. Moreover, CAT-DCs were able to suppress T-cells using indoleamine 2,3-dioxygenase (IDO), and induced IL10/IL17-secreting T-cells—a subtype reported to exert immunosuppression in acute myeloid leukemia. CAT-DCs also displayed significantly increased NADPH-oxidase-driven H2O2-production, enhancing low-density lipoprotein (LDL)-uptake. Blocking LDL-uptake restored maturation, and attenuated the immunosuppressive properties of CAT-DCs. Discussion: Here, we report a novel axis between H2O2- and LDL-metabolism controlling tolerogenic properties in moDCs. Given that moDCs are pivotal in tumor-rejection, and lipid-accumulation is associated with tumor-immune-escape, LDL-metabolism appears to play an important role in tumor-immunology

Global trends in the number and diversity of managed pollinator species

Cultivation of pollinator-dependent crops has expanded globally, increasing our reliance on insect pollination. This essential ecosystem service is provided by a wide range of managed and wild pollinators whose abundance and diversity are thought to be in decline, threatening sustainable food production. The Western honey bee (Apis mellifera) is amongst the best-monitored insects but the state of other managed pollinators is less well known. Here, we review the status and trends of all managed pollinators based on publicly accessible databases and the published literature. We found that, on a global scale, the number of managed A. mellifera colonies has increased by 85% since 1961, driven mainly by Asia. This contrasts with high reported colony overwinter mortality, especially in North America (average 26% since 2007) and Europe (average 16% since 2007). Increasing agricultural dependency on pollinators as well as threats associated with managing non-native pollinators have likely spurred interest in the management of alternative species for pollination, including bumble bees, stingless bees, solitary bees, and flies that have higher efficiency in pollinating specific crops. We identify 66 insect species that have been, or are considered to have the potential to be, managed for crop pollination, including seven bumble bee species and subspecies currently commercially produced mainly for the pollination of greenhouse-grown tomatoes and two species that are trap-nested in New Zealand. Other managed pollinators currently in use include eight solitary bee species (mainly for pollination services in orchards or alfalfa fields) and three fly species (mainly used in enclosures and for seed production). Additional species in each taxonomic category are under consideration for pollinator management. Examples include 15 stingless bee species that are able to buzz-pollinate, will fly in enclosures, and some of which have a history of management for honey production; their use for pollination is not yet established. To ensure sustainable, integrated pollination management in agricultural landscapes, the risks, as well as the benefits of novel managed pollinator species must be considered. We, therefore, urge the prioritization of biodiversity-friendly measures maintaining native pollinator species diversity to provide ecosystem resilience to future environmental changes.Fil: Osterman, Julia. Martin Luther University Halle-Wittenberg; Alemania. Helmholtz Centre for Environmental Research; AlemaniaFil: Aizen, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; Argentina. Institute for Advanced Study; AlemaniaFil: Biesmeijer, Jacobus C.. Leiden University; Países Bajos. Naturalis Biodiversity Center; Países BajosFil: Bosch, Jordi. Universitat Autònoma de Barcelona; EspañaFil: Howlett, Brad G.. The New Zealand Institute for Plant and Food Research Ltd.; Nueva ZelandaFil: Inouye, David W.. University of Maryland; Estados Unidos. Rocky Mountain Biological Laboratory; Estados UnidosFil: Jung, Chuleui. Andong National University; Corea del SurFil: Martins, Dino J.. University of Princeton; Estados UnidosFil: Medel, Rodrigo. Universidad de Chile; ChileFil: Pauw, Anton. Stellenbosch University; SudáfricaFil: Seymour, Colleen L.. University of Cape Town; Sudáfrica. South African National Biodiversity Institute; SudáfricaFil: Paxton, Robert J. German Centre for integrative Biodiversity Research; Alemania. Martin Luther University Halle-Wittenberg; Alemani

Agricultural policies exacerbate honeybee pollination service supply-demand mismatches across Europe

Declines in insect pollinators across Europe have raised concerns about the supply of pollination services to agriculture. Simultaneously, EU agricultural and biofuel policies have encouraged substantial growth in the cultivated area of insect pollinated crops across the continent. Using data from 41 European countries, this study demonstrates that the recommended number of honeybees required to provide crop pollination across Europe has risen 4.9 times as fast as honeybee stocks between 2005 and 2010. Consequently, honeybee stocks were insufficient to supply >90% of demands in 22 countries studied. These findings raise concerns about the capacity of many countries to cope with major losses of wild pollinators and highlight numerous critical gaps in current understanding of pollination service supplies and demands, pointing to a pressing need for further research into this issue

Novel Adjuvant Therapy for Ocular Melanoma

Background Malignant melanoma is the most common cancer of the eye in adults that originates either in the intra-ocular uveal tract or extra-ocular conjunctiva. Although the primary tumor can be treated successfully, no effective therapy for both metastatic conjunctival and uveal melanoma currently exits. Tumor-associated lymphangiogenesis and immune cell infiltration play a pivotal role in the development and therapeutic targeting of metastases. Project description Here, we provide an overview of current translational research on lymphangiogenesis and its therapeutic inhibition as well as modulation of immune cell infiltration by passive and active immunotherapy inmelanoma of the eye. Specifically, our previous and ongoing work on lymphangiogenesis and immune cells in ocular melanoma within the clinical research unit FOR 2240 (Lymph) Angiogenesis and Cellular Immunity in Inflammatory Diseases of the Eye is summarized. Conclusions Translational research on the modulation of tumor-associated lymphangiogenesis and immune cell infiltration could provide novel targets for adjuvant therapy in melanoma of the eye

An in vitro evaluation of fluorescein penetration into natural root surface carious lesions

In order to develop a method for detection and quantification of initial root surface carious lesions, the use of fluorescein sodium as a fluorescent dye is evaluated. The penetration depth of fluorescein sodium into human roots containing natural carious lesions was measured on approximately 130-mum-thick slices, cut in a direction perpendicular to the pulp. This depth was compared to the lesion depth that was measured on the same slice with transversal microradiography. The results indicate that fluorescein sodium in water penetrates into demineralized layers of root dentine even if a surface layer with a high mineral content is present. The penetation depth is about 1.1 times the microradiographically determined lesion depth

The Trojan Horse Tale Revisited: An Eye on Metastatic Spread of Carcinoma Cells

The metastatic spread of carcinoma cells is not fully understood. Here, we compare the peripheral blood mononuclear cells (PBMC) and intraocular metastatic cells in parotid gland carcinoma with the PBMCs of healthy donors by immunohistochemistry and flow cytometry. We found Ber-EP4 tumor marker-positive carcinoma cells in the aqueous humor of the patient's right eye and a CD45 and Ber-EP4-expressing PBMC population in his blood. These Ber-EP4-expressing cells exhibited a mono-cytic-myeloid phenotype with coexpression of CD11b, CD115, and the macrophage marker CD172a (SIRP-alpha). Uptake of pHrodogreen revealed their phagocytic activity. Our findings suggest that the tumor cells in the anterior chamber originally derived from cell fusions between tumor cells and myeloid cells in the peripheral blood. Thus, metastases of a solid malignancy could use monocytes-macrophages as the Trojan horse to enter the eye. (C) 2015 AACR

Hydrogen-Peroxide Synthesis and LDL-Uptake Controls Immunosuppressive Properties in Monocyte-Derived Dendritic Cells

Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H2O2) depletion. However, the effects on monocyte-derived dendritic cells (moDCs) are unknown. Methods: Monocytes from healthy donors were differentiated to moDCs in the presence of extracellular enzymatic H2O2-depletion (hereinafter CAT-DCs), and studied phenotypically and functionally. To elucidate the underlying molecular mechanisms, we analyzed H2O2- and LDL-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: CAT-DCs were of an immature DC phenotype, particularly characterized by impaired expression of the costimulatory molecules CD80/86. Moreover, CAT-DCs were able to suppress T-cells using indoleamine 2,3-dioxygenase (IDO), and induced IL10/IL17-secreting T-cells—a subtype reported to exert immunosuppression in acute myeloid leukemia. CAT-DCs also displayed significantly increased NADPH-oxidase-driven H2O2-production, enhancing low-density lipoprotein (LDL)-uptake. Blocking LDL-uptake restored maturation, and attenuated the immunosuppressive properties of CAT-DCs. Discussion: Here, we report a novel axis between H2O2- and LDL-metabolism controlling tolerogenic properties in moDCs. Given that moDCs are pivotal in tumor-rejection, and lipid-accumulation is associated with tumor-immune-escape, LDL-metabolism appears to play an important role in tumor-immunology