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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 26 April 2013, Vol.340(6131), pp.475-8
    Description: Protein secretion allows communication of distant cells in an organism and controls a broad range of physiological functions. We describe a quantitative, high-resolution mass spectrometric workflow to detect and quantify proteins that are released from immune cells upon receptor ligation. We quantified the time-resolved release of 775 proteins, including 52 annotated cytokines from only 150,000 primary Toll-like receptor 4-activated macrophages per condition. Achieving low picogram sensitivity, we detected secreted proteins whose abundance increased by a factor of more than 10,000 upon stimulation. Secretome to transcriptome comparisons revealed the transcriptionally decoupled release of lysosomal proteins. From genetic models, we defined secretory profiles that depended on distinct intracellular signaling adaptors and showed that secretion of many proinflammatory proteins is safeguarded by redundant mechanisms, whereas signaling adaptor synergy promoted the release of anti-inflammatory proteins.
    Keywords: Macrophage Activation ; Macrophages -- Immunology ; Mass Spectrometry -- Methods ; Proteins -- Metabolism ; Proteome -- Metabolism ; Toll-Like Receptor 4 -- Agonists
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 May 2012, Vol.109(20), pp.7853-8
    Description: In light of the marked global health impact of tuberculosis (TB), strong focus has been on identifying biosignatures. Gene expression profiles in blood cells identified so far are indicative of a persistent activation of the immune system and chronic inflammatory pathology in active TB. Definition of a biosignature with unique specificity for TB demands that identified profiles can differentiate diseases with similar pathology, like sarcoidosis (SARC). Here, we present a detailed comparison between pulmonary TB and SARC, including whole-blood gene expression profiling, microRNA expression, and multiplex serum analytes. Our analysis reveals that previously disclosed gene expression signatures in TB show highly similar patterns in SARC, with a common up-regulation of proinflammatory pathways and IFN signaling and close similarity to TB-related signatures. microRNA expression also presented a highly similar pattern in both diseases, whereas cytokines in the serum of TB patients revealed a slightly elevated proinflammatory pattern compared with SARC and controls. Our results indicate several differences in expression between the two diseases, with increased metabolic activity and significantly higher antimicrobial defense responses in TB. However, matrix metallopeptidase 14 was identified as the most distinctive marker of SARC. Described communalities as well as unique signatures in blood profiles of two distinct inflammatory pulmonary diseases not only have considerable implications for the design of TB biosignatures and future diagnosis, but they also provide insights into biological processes underlying chronic inflammatory disease entities of different etiology.
    Keywords: Gene Expression Profiling ; Biomarkers -- Blood ; Sarcoidosis -- Diagnosis ; Tuberculosis -- Diagnosis
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 08 May 2012, Vol.109(19), pp.E1153-62
    Description: Helicobacter pylori is a gastric pathogen responsible for a high disease burden worldwide. Deregulated inflammatory responses, possibly involving macrophages, are implicated in H. pylori-induced pathology, and microRNAs, such as miR-155, have recently emerged as crucial regulators of innate immunity and inflammatory responses. miR-155 is regulated by Toll-like receptor (TLR) ligands in monocyte-derived cells and has been shown to be induced in macrophages during H. pylori infection. Here, we investigated the regulation of miR-155 expression in primary murine bone marrow-derived macrophages (BMMs) during H. pylori infection and examined the downstream mRNA targets of this microRNA using microarray analysis. We report TLR2/4- and NOD1/2-independent up-regulation of miR-155, which was found to be dependent on the major H. pylori pathogenicity determinant, the type IV secretion system (T4SS). miR-155 expression was dependent on NF-κB signaling but was independent of CagA. Microarray analysis identified known gene targets of miR-155 in BMMs during H. pylori infection that are proapoptotic. We also identified and validated miR-155 binding sites in the 3' UTRs of the targets, Tspan14, Lpin1, and Pmaip1. We observed that H. pylori-infected miR-155(-/-) BMMs were significantly more susceptible to cisplatin DNA damage-induced apoptosis than were wild-type BMMs. Thus, our data suggest a function for the prototypical H. pylori pathogenicity factor, the T4SS, in the up-regulation of miR-155 in BMMs. We propose the antiapoptotic effects of miR-155 could enhance macrophage resistance to apoptosis induced by DNA damage during H. pylori infection.
    Keywords: Apoptosis ; Macrophages -- Metabolism ; Micrornas -- Genetics ; Toll-Like Receptors -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    In: Nature, 2017
    Description: The constant regeneration of stomach epithelium is driven by long-lived stem cells, but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover, while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues. Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2, is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5 cells, as well as adjacent, highly proliferative Lgr5 cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5 population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2/Lgr5 but not Lgr5 cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2 cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity.
    Keywords: Homeostasis ; Helicobacter Infections -- Metabolism ; Stem Cells -- Cytology ; Stomach -- Cytology ; Stromal Cells -- Metabolism ; Thrombospondins -- Metabolism;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 5
    Language: English
    In: Journal of Infectious Diseases, June 1, 2015, Vol.211(11), p.1831(11)
    Keywords: Bcg -- Dosage And Administration ; Tuberculosis -- Care And Treatment ; Autophagy (Cytology) -- Research ; Macrophages -- Research
    ISSN: 0022-1899
    Source: Cengage Learning, Inc.
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  • 6
    In: Molecular Microbiology, September 2011, Vol.81(5), pp.1144-1165
    Description: GcvB is one of the most highly conserved Hfq‐associated small RNAs in Gram‐negative bacteria and was previously reported to repress several ABC transporters for amino acids. To determine the full extent of GcvB‐mediated regulation in , we combined a genome‐wide experimental approach with biocomputational target prediction. Comparative pulse expression of wild‐type versus mutant sRNA variants revealed that GcvB governs a large post‐transcriptional regulon, impacting ∼1% of all genes via its conserved G/U‐rich domain R1. Complementary predictions of C/A‐rich binding sites in mRNAs and reporter fusion experiments increased the number of validated GcvB targets to more than 20, and doubled the number of regulated amino acid transporters. Unlike the previously described targeting via the single R1 domain, GcvB represses the glycine transporter CycA by exceptionally redundant base‐pairing. This novel ability of GcvB is focused upon the one target that could feedback‐regulate the glycine‐responsive synthesis of GcvB. Several newly discovered mRNA targets involved in amino acid metabolism, including the global regulator Lrp, question the previous assumption that GcvB simply acts to limit unnecessary amino acid uptake. Rather, GcvB rewires primary transcriptional control circuits and seems to act as a distinct regulatory node in amino acid metabolism.
    Keywords: Glycine -- Physiological Aspects ; Genetic Research -- Physiological Aspects ; Genomics -- Physiological Aspects ; Messenger Rna -- Physiological Aspects;
    ISSN: 0950-382X
    E-ISSN: 1365-2958
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(5), p.e64543
    Description: BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. It has been proposed that miRNAs play an important role in cancer development and progression. Their ability to affect multiple gene pathways by targeting various mRNAs makes them an interesting class of regulators. METHODOLOGY/PRINCIPAL FINDINGS: We have developed an algorithm, Classification based Analysis of Paired Expression data of RNA (CAPE RNA), which is capable of identifying altered miRNA-mRNA regulation between tissues samples that assigns interaction states to each sample without preexisting stratification of groups. The distribution of the assigned interaction states compared to given experimental groups is used to assess the quality of a predicted interaction. We demonstrate the applicability of our approach by analyzing urothelial carcinoma and normal bladder tissue samples derived from 24 patients. Using our approach, normal and tumor tissue samples as well as different stages of tumor progression were successfully stratified. Also, our results suggest interesting differentially regulated miRNA-mRNA interactions associated with bladder tumor progression. CONCLUSIONS/SIGNIFICANCE: The need for tools that allow an integrative analysis of microRNA and mRNA expression data has been addressed. With this study, we provide an algorithm that emphasizes on the distribution of samples to rank differentially regulated miRNA-mRNA interactions. This is a new point of view compared to current approaches. From bootstrapping analysis, our ranking yields features that build strong classifiers. Further analysis reveals genes identified as differentially regulated by miRNAs to be enriched in cancer pathways, thus suggesting biologically interesting interactions.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    In: EMBO Journal, 18 May 2011, Vol.30(10), pp.1977-1989
    Description: MicroRNAs have well‐established roles in eukaryotic host responses to viruses and extracellular bacterial pathogens. In contrast, microRNA responses to invasive bacteria have remained unknown. Here, we report cell type‐dependent microRNA regulations upon infection of mammalian cells with the enteroinvasive pathogen, Typhimurium. Murine macrophages strongly upregulate NF‐κB associated microRNAs; strikingly, these regulations which are induced by bacterial lipopolysaccharide (LPS) occur and persist regardless of successful host invasion and/or replication, or whether an inflammatory response is mounted, suggesting that microRNAs belong to the first line of anti‐bacterial defence. However, a suppression of the global immune regulator miR‐155 in endotoxin‐tolerant macrophages revealed that microRNA responses also depend on the status of infected cells. This study identifies the family as the common denominator of ‐regulated microRNAs in macrophages and epithelial cells, and suggests that repression of relieves cytokine IL‐6 and IL‐10 mRNAs from negative post‐transcriptional control. Our results establish a paradigm of microRNA‐mediated feed‐forward activation of inflammatory factors when mammalian cells are targeted by bacterial pathogens. This study describes the global mammalian micoRNA response to infection and the role of miRNAs in regulating the post‐transcriptional control of inflammatory cytokines.
    Keywords: Il‐10 ; Let‐7 ; Mir‐155 ; Mirna ; Salmonella
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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  • 9
    Language: English
    In: The Journal of infectious diseases, 01 December 2014, Vol.210(11), pp.1700-10
    Description: Epithelioid, foam, and multinucleated giant cells (MNGCs) are characteristics of tuberculosis granulomas, yet the precise genesis and functions of these transformed macrophages are unclear. We evaluated the role of platelets as drivers of macrophage transformation in mycobacterial infection. We employed flow cytometry and microscopy to assess cellular phenotype and phagocytosis. Immune assays allowed quantification of cytokines and chemokines, whereas gene microarray technology was applied to estimate global transcriptome alterations. Immunohistochemical investigations of tuberculosis granulomas substantiated our findings at the site of infection. Monocytes differentiated in presence of platelets (MP-Macs) acquired a foamy, epithelioid appearance and gave rise to MNGCs (MP-MNGCs). MP-Macs up-regulated activation markers, phagocytosed mycobacteria, and released abundant interleukin 10. Upon extended culture, MP-Macs shared transcriptional features with epithelioid cells and M2 macrophages and up-regulated CXCL5 transcripts. In line with this, CXCL5 concentrations were significantly increased in airways of active tuberculosis patients. The platelet-specific CD42b antigen was detected in MP-Macs, likewise in macrophages, MNGCs, and epithelioid cells within tuberculosis granulomas, along with the platelet aggregation-inducing factor PDPN. Platelets drive macrophage differentiation into MNGCs with characteristics of epithelioid, foam, and giant cells observed in tuberculosis granulomas. Our data define platelets as novel participants in tuberculosis pathogenesis.
    Keywords: Cxcl5 ; Macrophage ; Multinucleated Giant Cell ; Platelet ; Tuberculosis ; Immunomodulation ; Blood Platelets -- Metabolism ; Foam Cells -- Immunology ; Monocytes -- Immunology ; Mycobacterium -- Immunology
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 10
    Language: English
    In: Nature, August 28, 2014, Vol.512(7512), p.387(19)
    Description: The aryl hydrocarbon receptor (AhR) is a highly conserved ligand--dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns.
    Keywords: Transcription Factors – Physiological Aspects ; Hydrocarbons – Physiological Aspects ; Bacteria – Identification and Classification ; Bacteria – Physiological Aspects ; Biosensors – Physiological Aspects ; Cell Receptors – Physiological Aspects
    ISSN: 0028-0836
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