Yeast-mediated mRNA delivery polarizes immuno-suppressive macrophages towards an immuno-stimulatory phenotype

Seif, Michelle; Hoppstädter, Jessica; Breinig, Frank; Kiemer, Alexandra K.

doi:10.1016/j.ejpb.2017.03.008

Cited by 19 publications

(9 citation statements)

References 46 publications

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“…Under inflammatory conditions, repression of GILZ expression represents a regulatory mechanism that prolongs and/or increases pro‐inflammatory responses in human and murine macrophages (Hoppstädter et al., 2012, 2015). In contrast, the immunosuppressive phenotype of macrophages differentiated in the presence of M‐CSF and IL‐10 is associated with elevated GILZ expression (Seif, Hoppstädter, Breinig, & Kiemer, 2017). Based on these observations and the findings on GC homeostasis in aged mice shown within the present study, we hypothesized that GILZ might be downregulated during inflammaging.…”

Section: Discussionmentioning

confidence: 99%

Altered glucocorticoid metabolism represents a feature of macroph‐aging

et al. 2020

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The aging process is characterized by a chronic, low‐grade inflammatory state, termed “inflammaging.” It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging‐associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11‐dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid‐induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph‐aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging.

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Section: Discussionmentioning

confidence: 99%

Altered glucocorticoid metabolism represents a feature of macroph‐aging

et al. 2020

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“…Also, 1, 2, and 4 were moderately active against Erwinia persicina. Anticancer activities were determined against the human cancer cell lines A549 (lung carcinoma), Huh7.5 (hepatocellular carcinoma), MCF7 (breast adenocarcinoma), and SW620 (colorectal adenocarcinoma) by MTT assay [59]. Baikalomycins A and B showed moderate to weak effects on A549 and MCF7 cell viability ( Table 2).…”

Section: Biological Activities Of Baikalomycinsmentioning

confidence: 99%

Baikalomycins A-C, New Aquayamycin-Type Angucyclines Isolated from Lake Baikal Derived Streptomyces sp. IB201691-2A

et al. 2020

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Natural products produced by bacteria found in unusual and poorly studied ecosystems, such as Lake Baikal, represent a promising source of new valuable drug leads. Here we report the isolation of a new Streptomyces sp. strain IB201691-2A from the Lake Baikal endemic mollusk Benedictia baicalensis. In the course of an activity guided screening three new angucyclines, named baikalomycins A–C, were isolated and characterized, highlighting the potential of poorly investigated ecological niches. Besides that, the strain was found to accumulate large quantities of rabelomycin and 5-hydroxy-rabelomycin, known shunt products in angucyclines biosynthesis. Baikalomycins A–C demonstrated varying degrees of anticancer activity. Rabelomycin and 5-hydroxy-rabelomycin further demonstrated antiproliferative activities. The structure elucidation showed that baikalomycin A is a modified aquayamycin with β-d-amicetose and two additional hydroxyl groups at unusual positions (6a and 12a) of aglycone. Baikalomycins B and C have alternating second sugars attached, α-l-amicetose and α-l-aculose, respectively. The gene cluster for baikalomycins biosynthesis was identified by genome mining, cloned using a transformation-associated recombination technique and successfully expressed in S. albus J1074. It contains a typical set of genes responsible for an angucycline core assembly, all necessary genes for the deoxy sugars biosynthesis, and three genes coding for the glycosyltransferase enzymes. Heterologous expression and deletion experiments allowed to assign the function of glycosyltransferases involved in the decoration of baikalomycins aglycone.

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“…The ability of yeast cells to transport proteins, nucleic acids, or other biologically active agents into mammalian phagocytic cells has been shown repeatedly (Bazan, Breinig, Schmitt, & Breinig, 2014;Bazan et al, 2011;Seif, Hoppstädter, Breinig, & Kiemer, 2017;Walch, Breinig, Geginat, Schmitt, & Breinig, 2011;Walch-Rückheim, Kiefer, Geginat, Schmitt, & Breinig, 2016). To extend the described variety of applications, we investigated the capability of S. cerevisiae to associate with chitosan-coated PLGA nanoparticles to target the NPs specifically to phagocytes.…”

Section: Interaction Of Yeast Cells With Chitosan-coated Plga Partimentioning

confidence: 99%

“…Yeast cells have been repeatedly proven to be a remarkably efficient delivery vehicle for targeting a whole bunch of cargos to phagocytic cells in general and macrophages in particular (Bazan, Geginat, Breinig, Schmitt, & Breinig, ; Seif, Hoppstädter, Breinig, & Kiemer, ; Seif, Philippi, Breinig, Kiemer, & Hoppstadter, ; Stubbs et al, ; Walch, Breinig, Schmitt, & Breinig, ). Among the different yeast genera, the well‐characterized baker's yeast Saccharomyces cerevisiae possesses the GRAS status facilitating a possible application as a carrier system, thereby providing the advantages of a single cell organism including easy handling and genetic modification.…”

Section: Introductionmentioning

confidence: 99%

Targeted delivery of functionalized PLGA nanoparticles to macrophages by complexation with the yeast Saccharomyces cerevisiae

Kiefer

Jurisic

Dahlem

et al. 2019

Biotech & Bioengineering

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Nanoparticles (NPs) are able to deliver a variety of substances into eukaryotic cells.However, their usage is often hampered by a lack of specificity, leading to the undesired uptake of NPs by virtually all cell types. In contrast to this, yeast is known to be specifically taken up into immune cells after entering the body. Therefore, we investigated the interaction of biodegradable surface-modified poly(lactic-co-glycolic acid) (PLGA) particles with yeast cells to overcome the unspecificity of the particulate carriers. Cells of different Saccharomyces cerevisiae strains were characterized regarding their interaction with PLGA-NPs under isotonic and hypotonic conditions. The particles were shown to efficiently interact with yeast cells leading to stable NP/ yeast-complexes allowing to associate or even internalize compounds. Notably, applying those complexes to a coculture model of HeLa cells and macrophages, the macrophages were specifically targeted. This novel nano-in-micro carrier system suggests itself as a promising tool for the delivery of biologically active agents into phagocytic cells combining specificity and efficiency.

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Yeast-mediated mRNA delivery polarizes immuno-suppressive macrophages towards an immuno-stimulatory phenotype

Cited by 19 publications

References 46 publications

Altered glucocorticoid metabolism represents a feature of macroph‐aging

Altered glucocorticoid metabolism represents a feature of macroph‐aging

Baikalomycins A-C, New Aquayamycin-Type Angucyclines Isolated from Lake Baikal Derived Streptomyces sp. IB201691-2A

Targeted delivery of functionalized PLGA nanoparticles to macrophages by complexation with the yeast Saccharomyces cerevisiae

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