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BackgroundChemokine receptors and their corresponding ligands are key players of immunity by regulation of immune cell differentiation and migration. CXCR1 is a high‐affinity receptor for CXCL8. Differential expression of CXCR1 is... more
BackgroundChemokine receptors and their corresponding ligands are key players of immunity by regulation of immune cell differentiation and migration. CXCR1 is a high‐affinity receptor for CXCL8. Differential expression of CXCR1 is associated with a variety of human pathologies including cancer and inflammatory diseases. While various studies have highlighted the importance of CXCR1‐mediated CXCL8‐sensing for neutrophil trafficking and function, its role in B‐cell responses remains unsolved. Therefore, our aim was to investigate innate and adaptive antibody responses in CXCR1‐deficient mice.MethodsCell populations of the spleen and the peritoneal cavity were identified and quantified via flow cytometry. To investigate thymus‐independent (TI) and thymus‐dependent (TD) antibody responses, mice were immunized intraperitoneally with TNP‐Ficoll, Pneumovax23, and TNP‐Chicken Gamma Globulin. Mice were bled before as well as 7 and 14 days after vaccination to collect serum. Serum antibody levels overtime were analyzed according to their specificity by enzyme‐linked immunosorbent assay. B‐1 cell functionality was examined by IL‐5/IL‐5Rα‐dependent stimulation of peritoneal and splenic cells in vitro. To analyze CXCR1/2‐expression, CD19+ splenocytes were enriched by magnetic‐activated cell sorting before isolation of total RNA contents, followed by reverse transcription and real‐time polymerase chain reaction.ResultsThe distribution of natural B‐1 cell populations was disturbed in the absence of CXCR1, while their responsiveness towards TI antigens and in vitro stimulation remained functional. Besides, CXCR1‐deficiency was accompanied by increased frequencies of follicular B‐2 cells in the spleen. Interestingly, these mice produced elevated levels of antigen‐specific IgG1 upon TD immunization and harbored a significantly enlarged proportion of CXCR5‐expressing T helper (H) cells. CXCR1‐expression was detectable in CD19+ splenocytes derived from wild‐type, but not CXCR1‐deficient mice.ConclusionOur data demonstrate a previously unknown relevance of CXCR1 for the production of specific IgG1 in response to vaccination. These findings identify CXCR1 as a promising candidate for future studies on the regulation of adaptive antibody responses.
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In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very early stages. Recent research has revealed... more
In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very early stages. Recent research has revealed a co-dependence between planar polarization of some cell types and cilium positioning at the surface of cells. This important role of the primary cilium in mammalian cells is in contrast with its absence from Drosophila melanogaster PCP establishment. Here, we show that deletion of GTP-binding protein alpha-i subunit 3 (Gαi3) and mammalian Partner of inscuteable (mPins) disrupts the migration of the kinocilium at the surface of cochlear hair cells and affects hair bundle orientation and shape. Inhibition of G-protein function in vitro leads to kinocilium migration defects, PCP phenotype and abnormal hair bundle morphology. We show that Gαi3/mPins are expressed in an apical and distal asymmetrical domain, which is opposite and complementary to an aPKC/Par-3/Par-6b expression domain, and non-overlapping with the core PCP protein Vangl2. Thus G-protein-dependent signalling controls the migration of the cilium cell autonomously, whereas core PCP signalling controls long-range tissue PCP.
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ABSTRACT Background Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear. Methods We... more
ABSTRACT Background Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear. Methods We performed an analysis of the Scientific Registry of Transplant Recipients database. Kidney transplant recipients were categorized according to body mass index (BMI) categories and immunosuppressive protocols: (i) tacrolimus/mycophenolate mofetil (Tac-MMF), (ii) mTOR-inhibitor/Tac (mTORi-Tac), (iii) mTORi/cyclosporin (mTORi-Cyc) and (iv) mTORi-MMF. Results Graft recipients with advanced obesity (BMI ≥35 kg/m2) exhibited significantly lower rates of acute rejection during the first year after transplantation in the mTORi-Tac (6.4%) group compared with Tac-MMF (11.2%). Obesity class 1 (30 < BMI < 35 kg/m2) was associated with a significant risk of acute rejection for the mTORi-Tac group [obesity class 1 hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.21–2.62, P = .003]. A similar trend was observed in the Tac-MMF group for advanced obesity HR 1.29; 95% CI 0.96–1.73, P = .087). For the Tac-MMF group, recipients with both overweight and obesity had significantly impaired survival due to cardiovascular events and also increased mortality due to infection in advanced obesity. Combination of mTORi and calcineurin inhibitor was associated with lower rejection rates and stable long-term kidney function while reducing cardiovascular side effects linked to calcineurin inhibitors in obese kidney graft recipients. Conclusion These results are critical for the growing number of obese graft recipients and warrant prospective evaluation.
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Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P.... more
Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases.
Research Interests: Microbiology, Immunology, Cystic Fibrosis, Biology, Innate immunity, and 15 moreMedicine, Humans, Mice, Female, Animals, Male, Lung, Pseudomonas aeruginosa, Chemokine, Neutrophils, Pseudomonas Aeruginosa, Host Pathogen Interactions, Innate Immune System, Medical and Health Sciences, and Pulmonary Disease Chronic Obstructive
Research Interests: Immunology, Biology, Innate immunity, Medicine, Dendritic Cells, and 15 moreSignal Transduction, Toll like receptor signaling, Hematopoietic Stem Cells, Cell Differentiation, Mice, Animals, Sepsis, Haematopoiesis, Ciencias Biológicas, Immune system, Monocytes, Inmunología, Bacterial Infection, Innate Immune System, and Interferon gamma
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Infection of mice with Listeria monocytogenes results in a strong T‐cell response that is critical for an efficient defense. Here, we demonstrate that the adapter protein SLy1 (SH3‐domain protein expressed in Lymphocytes 1) is essential... more
Infection of mice with Listeria monocytogenes results in a strong T‐cell response that is critical for an efficient defense. Here, we demonstrate that the adapter protein SLy1 (SH3‐domain protein expressed in Lymphocytes 1) is essential for the generation of a fully functional T‐cell response. The lack of SLy1 leads to reduced survival rates of infected mice. The increased susceptibility of SLy1 knock‐out (KO) mice was caused by reduced proliferation of differentiated T cells. Ex vivo analyses of isolated SLy1 KO T cells displayed a dysregulation of Forkhead box protein O1 shuttling after TCR signaling, which resulted in an increased expression of cell cycle inhibiting genes, and therefore, reduced expansion of the T‐cell population. Forkhead box protein O1 shuttles to the cytoplasm after phosphorylation in a protein complex including 14‐3‐3 proteins. Interestingly, we observed a similar regulation for the adapter protein SLy1, where TCR stimulation results in SLy1 phosphorylation and SLy1 export to the cytoplasm. Moreover, immunoprecipitation analyses revealed a binding of SLy1 to 14‐3‐3 proteins. Altogether, this study describes SLy1 as an immunoregulatory protein, which is involved in the generation of adaptive immune responses during L. monocytogenes infection, and provides a model of how SLy1 regulates T‐cell proliferation.
Research Interests: Immunology, Flow Cytometry, Biology, Cell Biology, Innate immunity, and 14 moreMedicine, Western blotting, Cell Differentiation, Mice, Female, Animals, Listeria monocytogenes, Immunoprecipitation, T lymphocytes, Listeriosis, Transfection, Cell Proliferation, Knockout Mice, and reverse transcriptase polymerase chain reaction
Research Interests: Reproduction, Biology, Toxoplasma, Cell Biology, Confocal Microscopy, and 14 moreMedicine, Multidisciplinary, Toxoplasma gondii, Western blotting, Mice, Animals, Astrocytes, Fluorescent Antibody Technique, Immune system, Host Pathogen Interactions, Lymphocytes, Knockout Mice, Gtp Binding Proteins, and Interferon gamma
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Research Interests: Immunology, Biology, Cell Biology, Apoptosis, Medicine, and 15 moreSignal Transduction, Cell line, Cell Differentiation, Mice, Animals, T cell development, Research article, Programmed cell death, Ribosomal Protein, Bone marrow stromal cells, Protein requirement, Inhibitor of apoptosis proteins, Double Negative, Thymus Gland, and B cell
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The Lpl proteins represent a class of lipoproteins that was first described in the opportunistic bacterial pathogen Staphylococcus aureus, where they contribute to pathogenicity by enhancing F-actin levels of host epithelial cells and... more
The Lpl proteins represent a class of lipoproteins that was first described in the opportunistic bacterial pathogen Staphylococcus aureus, where they contribute to pathogenicity by enhancing F-actin levels of host epithelial cells and thereby increasing S. aureus internalization. The model Lpl protein, Lpl1 was shown to interact with the human heat shock proteins Hsp90α and Hsp90ß, suggesting that this interaction may trigger all observed activities. Here we synthesized Lpl1-derived peptides of different lengths and identified two overlapping peptides, namely, L13 and L15, which interacted with Hsp90α. Unlike Lpl1, the two peptides not only decreased F-actin levels and S. aureus internalization in epithelial cells but they also decreased phagocytosis by human CD14+ monocytes. The well-known Hsp90 inhibitor, geldanamycin, showed a similar effect. The peptides not only interacted directly with Hsp90α, but also with the mother protein Lpl1. While L15 and L13 significantly decreased let...
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BackgroundInfections with Streptococcus pneumoniae can cause severe diseases in humans including pneumonia. Although guidelines for vaccination have been established, S. pneumoniae is still responsible for a serious burden of disease... more
BackgroundInfections with Streptococcus pneumoniae can cause severe diseases in humans including pneumonia. Although guidelines for vaccination have been established, S. pneumoniae is still responsible for a serious burden of disease around the globe. Currently, two pneumococcal immunizations are available, namely the pure polysaccharide vaccine Pneumovax23 (P23) and the conjugate‐vaccine Prevenar13 (PCV13). We recently reported impaired thymus‐independent antibody responses towards P23 in mice overexpressing the immunoinhibitory adapter SLy2. The purpose of this study was to evaluate adaptive B‐cell responses towards the thymus‐dependent vaccine PCV13 in SLy2‐overexpressing mice and to study their survival rate during pneumococcal lung infection. Moreover, we investigated B‐cell developmental stages within the bone marrow (BM) in the context of excessive SLy2‐expression.MethodsB‐cell subsets and their surface immune globulins were investigated by flow cytometry. For class‐switch as...
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Inhibitory G proteins (Giproteins) are highly homologous but play distinct biological roles. However, their isoform-specific detection remains challenging. To facilitate the analysis of Gαi3expression, we generated aGnai3-iresGFP... more
Inhibitory G proteins (Giproteins) are highly homologous but play distinct biological roles. However, their isoform-specific detection remains challenging. To facilitate the analysis of Gαi3expression, we generated aGnai3-iresGFP reporter mouse line. An internal ribosomal entry site (IRES) was inserted behind the stop-codon of theGnai3gene to initiate simultaneous translation of the GFP cDNA together with Gαi3. The expression of GFP was confirmed in spleen and thymus tissue by immunoblot analysis. Importantly, the GFP knock-in (ki) did not alter Gαi3expression levels in all organs tested including spleen and thymus compared to wild-type littermates. Flow cytometry of thymocytes, splenic and blood cell suspensions revealed significantly higher GFP fluorescence intensities in homozygous ki/ki animals compared to heterozygous mice (+/ki). Using cell-type specific surface markers GFP fluorescence was assigned to B cells, T cells, macrophages and granulocytes from both splenic and blo...
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Myeloid‐derived suppressor cells (MDSCs) are key regulators of immunity that initially have been defined by their ability to potently suppress T‐cell responses. Recent studies collectively demonstrate that the suppressive activity of... more
Myeloid‐derived suppressor cells (MDSCs) are key regulators of immunity that initially have been defined by their ability to potently suppress T‐cell responses. Recent studies collectively demonstrate that the suppressive activity of MDSCs is not limited to T cells, but rather affects a broad range of immune cell subsets. However, relatively few studies have assessed the impact of MDSCs on B cells, particularly in the human context. Here, we report that human monocytic MDSCs (M‐MDSCs) significantly interfere with human B‐cell proliferation and function in vitro. We further show that the inhibition occurs independent of direct cell‐contact and involves the expression of suppressive mediators such as indoleamine 2, 3‐dioxygenase (IDO), arginase‐1 (Arg1), and nitric oxide (NO). In addition, our studies demonstrate that the suppression of B cells by M‐MDSCs is paralleled by a skewing in B‐cell phenotype and gene expression signatures. M‐MDSCs induced the downregulation of key surface ma...
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Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence... more
Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted.
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Sterile alpha motif (SAM) domains are protein interaction modules that are involved in a diverse range of biological functions such as transcriptional and translational regulation, cellular signalling, and regulation of developmental... more
Sterile alpha motif (SAM) domains are protein interaction modules that are involved in a diverse range of biological functions such as transcriptional and translational regulation, cellular signalling, and regulation of developmental processes. SH3 domain-containing protein expressed in lymphocytes 1 (SLy1) is involved in immune regulation and contains a SAM domain of unknown function. In this report, the structure of the SLy1 SAM domain was solved and revealed that this SAM domain forms a symmetric homodimer through a novel interface. The interface consists primarily of the two long C-terminal helices, α5 and α5′, of the domains packing against each other. The dimerization is characterized by a dissociation constant in the lower micromolar range. A SLy1 SAM domain construct with an extended N-terminus containing five additional amino acids of the SLy1 sequence further increases the stability of the homodimer, making the SLy1 SAM dimer two orders of magnitude more stable than previo...
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Phosphoinositide 3-kinase γ (PI3Kγ) and PI3Kδ are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110γ and p110δ of PI3Kγ... more
Phosphoinositide 3-kinase γ (PI3Kγ) and PI3Kδ are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110γ and p110δ of PI3Kγ and PI3Kδ in p110γ/δ(-/-) mice leads to defective B- and T-cell homeostasis. Here we examined the role of p110γ and p110δ in the homeostasis of neutrophils by analyzing p110γ(-/-), p110δ(-/-) and p110γ/δ(-/-) mice. Neutrophils and T cells in leukocyte suspensions from the bone marrow (BM), blood, spleen and lung were analyzed by flow cytometry. Serum concentrations of IL-17, of the neutrophilic growth factor G-CSF, and of the neutrophil mobilizing CXC chemokines CXCL1/KC and CXCL2/MIP-2 were measured by Bio-Plex assay. Production of G-CSF and CXCL1/KC by IL-17-stimulated primary lung tissue cells were determined by ELISA, whereas IL-17-dependent signaling in lung tissue cells was analyzed by measuring Akt phosphorylation using immunoblot. We found tha...
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Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of... more
Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.
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Asthma is the most common chronic disease in childhood. Although several therapeutic options are currently available to control the symptoms, many drugs have significant side effects and asthma remains an incurable disease. Microbial... more
Asthma is the most common chronic disease in childhood. Although several therapeutic options are currently available to control the symptoms, many drugs have significant side effects and asthma remains an incurable disease. Microbial exposure in early life reduces the risk of asthma and several studies have suggested protective effects of Toll-like receptor (TLR) activation. We showed previously that modified mRNA provides a safe and efficient therapeutic tool for in vivo gene supplementation. Since current asthma drugs do not take patient specific immune and TLR backgrounds into consideration, treatment with tailored mRNA could be an attractive approach to account for the patient's individual asthma phenotype. Therefore, we investigated the effect of a preventative treatment with combinations of Tlr1, Tlr2 and Tlr6 mRNA in a House Dust Mite-induced mouse model of asthma. We used chemically modified mRNA which is-in contrast to conventional viral vectors-non-integrating and high...
Research Interests: Immunology, Biology, Asthma, Medicine, Multidisciplinary, and 7 moreToll Like Receptors, Mice, Female, Animals, PLoS one, In Vivo, and TLR
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Fluorescently labeled Ly6G antibodies enable the tracking of neutrophils in mice, whereas purified anti-Ly6G rapidly depletes neutrophils from the circulation. The mechanisms underlying neutrophil depletion are still under debate. Here,... more
Fluorescently labeled Ly6G antibodies enable the tracking of neutrophils in mice, whereas purified anti-Ly6G rapidly depletes neutrophils from the circulation. The mechanisms underlying neutrophil depletion are still under debate. Here, we examined how identical Ly6G antibodies coupled to different fluorochromes affect neutrophil fate in vivo. BM cells stained with Ly6G antibodies were injected into mice. The number of retrieved anti-Ly6G-FITC+ cells was reduced significantly in comparison with anti-Ly6G-APC+ or anti-Ly6G-PE+ cells. Flow cytometry and multispectral imaging flow cytometry analyses revealed that anti-Ly6G-FITC+ neutrophils were preferentially phagocytosed by BMMs in vitro and by splenic, hepatic, and BM macrophages in vivo. Direct antibody injection of anti-Ly6G-FITC but not anti-Ly6G-PE depleted neutrophils to the same degree as purified anti-Ly6G, indicating that the FITC-coupled antibody eliminates neutrophils by a similar mechanism as the uncoupled antibody. With ...
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In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is... more
In view of the rapid preclinical development of cell-based therapies for neurodegenerative disorders, traumatic brain injury, and tumors, the safe and efficient delivery and targeting of therapeutic cells to the central nervous system is critical for maintaining therapeutic efficacy and safety in the respective disease models. Our previous data demonstrated therapeutically efficacious and targeted delivery of mesenchymal stem cells (MSCs) to the brain in the rat 6-hydroxydopamine model of Parkinson's disease (PD). The present study examined delivery of bone marrow-derived MSCs, macrophages, and microglia to the brain in a transgenic model of PD [(Thy1)-h[A30P] αS] and an APP/PS1 model of Alzheimer's disease (AD) via intranasal application (INA). INA of microglia in naive BL/6 mice led to targeted and effective delivery of cells to the brain. Quantitative PCR analysis of eGFP DNA showed that the brain contained the highest amount of eGFP-microglia (up to 2.1 × 10(4)) after IN...
Research Interests: Flow Cytometry, Macrophages, Medicine, Biological Sciences, Hippocampus, and 15 moreCell Differentiation, Brain, Mice, Female, Animals, Male, Bone marrow, Mesenchymal Stem Cell, Cell Transplantation, Biological markers, Intranasal Administration, Alzheimer Disease, Mesenchymal Stromal Cells, Bone Marrow Cells, and Medical and Health Sciences
Research Interests: Microbiology, Immunology, Medical Microbiology, Biology, Cell Biology, and 15 moreInnate immunity, Medicine, Cell separation, Dendritic Cells, Mice, Female, Animals, Bacteria, Ciencias Biológicas, Neutrophils, Homeostasis, Phagocytes, Innate Immune System, Adoptive Transfer, and Adoptive Cell Transfer
The major human pathogen Staphylococcus aureus has very efficient strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant S. aureus depends on phenol-soluble modulin (PSM)... more
The major human pathogen Staphylococcus aureus has very efficient strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant S. aureus depends on phenol-soluble modulin (PSM) peptide toxins, which are known to attract and lyse neutrophils. However, their influences on other immune cells remain elusive. In this study, we analyzed the impact of PSMs on dendritic cells (DCs) playing an essential role in linking innate and adaptive immunity. In human neutrophils, PSMs exert their function by binding to the formyl peptide receptor (FPR) 2. We show that mouse DCs express the FPR2 homolog mFPR2 as well as its paralog mFPR1 and that PSMs are chemoattractants for DCs at noncytotoxic concentrations. PSMs reduced clathrin-mediated endocytosis and inhibited TLR2 ligand-induced secretion of the proinflammatory cytokines TNF, IL-12, and IL-6, while inducing IL-10 secretion by DCs. As a consequence, treatment with PSMs impaired the capacity ...
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The interactions between pathogens and hosts lead to a massive upregulation of antimicrobial host effector molecules. Among these, the 65 kDa guanylate binding proteins (GBPs) are interesting candidates as intricate components of the host... more
The interactions between pathogens and hosts lead to a massive upregulation of antimicrobial host effector molecules. Among these, the 65 kDa guanylate binding proteins (GBPs) are interesting candidates as intricate components of the host effector molecule repertoire. Members of the GBP family are highly conserved in vertebrates. Previous reports indicate an antiviral activity of human GBP1 (hGBP1) and murine GBP2 (mGBP2). We recently demonstrated that distinct murine GBP (mGBP) family members are highly upregulated uponToxoplasma gondiiinfection and localize around the intracellular protozoaT. gondii. Moreover, we characterised five new mGBP family members within the murine 65 kDa GBP family. Here, we identified a new mGBP locus namedmGbp11. Based on bacterial artificial chromosome (BAC), expressed sequence tag (EST), and RT-PCR analyses this study provides a detailed insight into the genomic localization and organization of the mGBPs. These analyses revealed a 166-kb spanning regi...
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Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We... more
Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We investigated the role of extracellular platelet nucleotide signaling in the context of IIR and defined a cybernetic circle, including description of feedback loops. Cybernetic circles seek to integrate different levels of information to understand how biological systems function. Our study specifies the components of the cybernetic system of platelets in IIR and describes the theoretical progression of IIR passing the cybernetic cycle with positive and negative feedback loops based on nucleotide-dependent signaling and functional regulation. The cybernetic components and feedback loops were explored by cytometry, immunohistological staining, functional blocking antibodies, and ADP/ATP measurements. Using several ex vivo and in vivo approaches we confirmed cybe...
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Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through... more
Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through cyclooxygenase-2 and arginase-1 pathways. Here, we further dissected this mechanism by studying the role and therapeutic relevance of the downstream mediator prostaglandin E2 receptor 4 (EP4) in a murine model of asthma. We adoptively transferred MDSCs generated using an EP4 agonist in a murine model of asthma and studied the consequences on airway inflammation. Furthermore, pegylated human arginase-1 was used to model MDSC effector activities. We demonstrate that the selective EP4 agonist L-902,688 increased the number and suppressive activity of MDSCs through arginase-1 and nitric oxide synthase-2. These results showed that adoptive transfer of EP4-primed MDSCs, EP4 agonism alone or arginase-1 administration ameliorated lung inflammatory responses a...