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3. Kombinierte Anästhesieverfahren

Author

Brodner, Gerhard, Bürkle, Hartmut, Van Aken, Hugo, Gottschalk, Antje, Werner, Christian, Section editor, Rossaint, Rolf, editor, Werner, Christian, editor, and Zwißler, Bernhard, editor

Published
2019
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4. Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response.

Author

Rossaint, Jan, Kühne, Katharina, Skupski, Jennifer, Van Aken, Hugo, Looney, Mark R, Hidalgo, Andres, and Zarbock, Alexander

Subjects
Blood Platelets, Neutrophils, Animals, Mice, Inbred C57BL, Mice, Knockout, Escherichia coli Infections, Pneumonia, Bacterial, Thromboxane A2, Membrane Glycoproteins, P-Selectin, Platelet Glycoprotein GPIb-IX Complex, Immunity, Biological Transport, Platelet Adhesiveness, Male, Cyclooxygenase 1, Extracellular Vesicles, Mice, Inbred C57BL, Knockout, Pneumonia, Bacterial
Abstract

The innate immune response to bacterial infections requires the interaction of neutrophils and platelets. Here, we show that a multistep reciprocal crosstalk exists between these two cell types, ultimately facilitating neutrophil influx into the lung to eliminate infections. Activated platelets adhere to intravascular neutrophils through P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1)-mediated binding, a primary interaction that allows platelets glycoprotein Ibα (GPIbα)-induced generation of neutrophil-derived extracellular vesicles (EV). EV production is directed by exocytosis and allows shuttling of arachidonic acid into platelets. EVs are then specifically internalized into platelets in a Mac1-dependent fashion, and relocated into intracellular compartments enriched in cyclooxygenase1 (Cox1), an enzyme processing arachidonic acid to synthesize thromboxane A2 (TxA2). Finally, platelet-derived-TxA2 elicits a full neutrophil response by inducing the endothelial expression of ICAM-1, intravascular crawling, and extravasation. We conclude that critical substrate-enzyme pairs are compartmentalized in neutrophils and platelets during steady state limiting non-specific inflammation, but bacterial infection triggers regulated EV shuttling resulting in robust inflammation and pathogen clearance.

Published
2016

24. FGF23 signaling impairs neutrophil recruitment and host defense during CKD

Author

Rossaint, Jan, Oehmichen, Jessica, Van Aken, Hugo, Reuter, Stefan, Pavenstadt, Hermann J., Meersch, Melanie, Unruh, Mark, and Zarbock, Alexander

Subjects
Chronic kidney failure -- Risk factors -- Genetic aspects, Neutrophils -- Analysis, Cellular signal transduction -- Research, Health care industry
Abstract

Chronic kidney disease (CKD) has been associated with impaired host response and increased susceptibility to infections. Leukocyte recruitment during inflammation must be tightly regulated to protect the host against pathogens. FGF23 levels are increased in blood during CKD, and levels of this hormone have been associated with a variety of adverse effects in CKD patients. Here, we have shown that CKD impairs leukocyte recruitment into inflamed tissue and host defense in mice and humans. FGF23 neutralization during CKD in murine models restored leukocyte recruitment and host defense. Intravital microscopy of animals with chronic kidney failure showed that FGF23 inhibits chemokine- activated leukocyte arrest on the endothelium, and downregulation of FGF receptor 2 (FGFR2) on PMNs rescued host defense in these mice. In vitro, FGF23 inhibited PMN adhesion, arrest under flow, and transendothelial migration. Mechanistically, FGF23 binding to FGFR2 counteracted selectin- and chemokine-triggered [β.sub.2] integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rap1. Moreover, knockdown of PKA abolished the inhibitory effect of FGF23 on integrin activation. Together, our data reveal that FGF23 acts directly on PMNs and dampens host defense by direct interference with chemokine signaling and integrin activation., Introduction Chronic kidney disease (CKD) is a common condition in developed countries, and the incidence can be high as 400 cases per 1,000,000 inhabitants (1). Loss of renal function is [...]

Published
2016
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44. Chemokine homeostasis vs. chemokine presentation during severe acute lung injury: the other side of the Duffy antigen receptor for chemokines

Author

Zarbock, Alexander, Bishop, Jeffrey, Muller, Helena, Schmolke, Mirco, Buschmann, Kirsten, Van Aken, Hugo, and Singbartl, Kai

Subjects
Acute respiratory distress syndrome -- Physiological aspects, Acute respiratory distress syndrome -- Genetic aspects, Acute respiratory distress syndrome -- Care and treatment, Acute respiratory distress syndrome -- Research, Chemokines -- Physiological aspects, Chemokines -- Genetic aspects, Chemokines -- Research, Homeostasis -- Research, Homeostasis -- Physiological aspects, Homeostasis -- Genetic aspects, Biological sciences
Abstract

Acute lung injury (ALI) still poses a major challenge in critical care medicine. Neutrophils, platelets, and chemokines are all considered key components in the development of ALI. The Duffy antigen receptor for chemokines (DARC) is thought to be involved in scavenging, transendothelial transport, and presentation of neutrophil-specific chemokines. DARC is expressed on endothelial cells and erythrocytes but not on leukocytes. Here, we show that DARC is crucial for chemokine-mediated leukocyte recruitment in vivo. However, we also demonstrate that changes in chemokine and chemokine receptor homeostasis, associated with Darc gene deficiency, exert strong anti-inflammatory effects. Neutrophils from Darc gene-deficient ([Darc.sup.-/-]) mice display a more prolonged downregulation of CXCR2 during severe inflammation than neutrophils from wild-type mice. In a CXCR2-dependent model of acid-induced ALI, Dare gene deficiency prevents ALI. [Darc.sup.-/-] mice demonstrate fully preserved oxygenation, only a small increase in vascular permeability, and a complete lack of pulmonary neutrophil recruitment. Further analysis reveals that only neutrophils but neither endothelial cells nor erythrocytes from [Darc.sup.-/-] mice confer protection from ALI. The protection appears to be due to abolished pulmonary recruitment of neutrophils from [Darc.sup.-/-] mice. The generation of neutrophil-platelet aggregates, a key mechanism in both pulmonary neutrophil recruitment and thrombus formation, is also affected by altered CXCR2 homeostasis in [Darc.sup.-/-] mice. CXCR2 blockade enhances the formation of platelet-neutrophil aggregates and thereby corrects a formerly unknown bleeding defect in [Darc.sup.-/-] mice. In summary, our study suggests that chemokine/ chemokine receptor homeostasis plays a previously unrecognized and crucial role in severe ALI. endothelial cells; erythrocytes doi:10.1152/ajplung.00224.2009

Published
2010

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