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2. Author Correction: Vascular surveillance by haptotactic blood platelets in inflammation and infection

Author

Nicolai, Leo, Schiefelbein, Karin, Lipsky, Silvia, Leunig, Alexander, Hoffknecht, Marie, Pekayvaz, Kami, Raude, Ben, Marx, Charlotte, Ehrlich, Andreas, Pircher, Joachim, Zhang, Zhe, Saleh, Inas, Marel, Anna-Kristina, Löf, Achim, Petzold, Tobias, Lorenz, Michael, Stark, Konstantin, Pick, Robert, Rosenberger, Gerhild, Weckbach, Ludwig, Uhl, Bernd, Xia, Sheng, Reichel, Christoph Andreas, Walzog, Barbara, Schulz, Christian, Zheden, Vanessa, Bender, Markus, Li, Rong, Massberg, Steffen, and Gaertner, Florian

Published
2022
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3. Vascular surveillance by haptotactic blood platelets in inflammation and infection

Author

Nicolai, Leo, Schiefelbein, Karin, Lipsky, Silvia, Leunig, Alexander, Hoffknecht, Marie, Pekayvaz, Kami, Raude, Ben, Marx, Charlotte, Ehrlich, Andreas, Pircher, Joachim, Zhang, Zhe, Saleh, Inas, Marel, Anna-Kristina, Löf, Achim, Petzold, Tobias, Lorenz, Michael, Stark, Konstantin, Pick, Robert, Rosenberger, Gerhild, Weckbach, Ludwig, Uhl, Bernd, Xia, Sheng, Reichel, Christoph Andreas, Walzog, Barbara, Schulz, Christian, Zheden, Vanessa, Bender, Markus, Li, Rong, Massberg, Steffen, and Gaertner, Florian

Published
2020
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6. A novel OSA-related model of intermittent hypoxia in endothelial cells under flow reveals pronounced inflammatory pathway activation

Author

Müller, Martin B., primary, Stihl, Clemens, additional, Schmid, Annika, additional, Hirschberger, Simon, additional, Mitsigiorgi, Rea, additional, Holzer, Martin, additional, Patscheider, Martin, additional, Weiss, Bernhard G., additional, Reichel, Christoph, additional, Hübner, Max, additional, and Uhl, Bernd, additional

Published
2023
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7. Vitronectin promotes immunothrombotic dysregulation in the venular microvasculature

Author

Uhl, Bernd, primary, Haring, Florian, additional, Slotta-Huspenina, Julia, additional, Luft, Joshua, additional, Schneewind, Vera, additional, Hildinger, Jonas, additional, Wu, Zhengquan, additional, Steiger, Katja, additional, Smiljanov, Bojan, additional, Batcha, Aarif M. N., additional, Keppler, Oliver T., additional, Hellmuth, Johannes C., additional, Lahmer, Tobias, additional, Stock, Konrad, additional, Weiss, Bernhard G., additional, Canis, Martin, additional, Stark, Konstantin, additional, Bromberger, Thomas, additional, Moser, Markus, additional, Schulz, Christian, additional, Weichert, Wilko, additional, Zuchtriegel, Gabriele, additional, and Reichel, Christoph A., additional

Published
2023
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8. A Novel Experimental Approach for In Vivo Analyses of the Salivary Gland Microvasculature

Author

Uhl, Bernd, Braun, Constanze, Dominik, Julian, Luft, Joshua, Canis, Martin, and Reichel, Christoph A.

Subjects
Inflammation, Male, leukocyte trafficking, microvascular permeability, Microscopy, Confocal, Tumor Necrosis Factor-alpha, Submandibular Gland, microcirculation, salivary gland, Flow Cytometry, Antibodies, immunology, Capillary Permeability, Mice, Inbred C57BL, Chemotaxis, Leukocyte, Microscopy, Fluorescence, Multiphoton, Phenotype, Microvessels, Leukocytes, Animals, Leukocyte Rolling, in vivo imaging, Cell Adhesion Molecules, Original Research, Signal Transduction
Abstract

Microvascular dysfunction plays a fundamental role in the pathogenesis of salivary gland disorders. Restoring and preserving microvascular integrity might therefore represent a promising strategy for the treatment of these pathologies. The mechanisms underlying microvascular dysfunction in salivary glands, however, are still obscure, partly due to the unavailability of adequate in vivo models. Here, we present a novel experimental approach that allows comprehensive in vivo analyses of the salivary gland microvasculature in mice. For this purpose, we employed different microscopy techniques including multi-photon in vivo microscopy to quantitatively analyze interactions of distinct immune cell subsets in the submandibular gland microvasculature required for their infiltration into the surrounding parenchyma and their effects on microvascular function. Confocal microscopy and multi-channel flow cytometry in tissue sections/homogenates complemented these real-time analyses by determining the molecular phenotype of the participating cells. To this end, we identified key adhesion and signaling molecules that regulate the subset- and tissue-specific trafficking of leukocytes into inflamed glands and control the associated microvascular leakage. Hence, we established an experimental approach that allows in vivo analyses of microvascular processes in healthy and diseased salivary glands. This enables us to delineate distinct pathogenetic factors as novel therapeutic targets in salivary gland diseases.

Published
2022

11. Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression

Author

Mittmann, Laura A, primary, Haring, Florian, additional, Schaubächer, Johanna B, additional, Hennel, Roman, additional, Smiljanov, Bojan, additional, Zuchtriegel, Gabriele, additional, Canis, Martin, additional, Gires, Olivier, additional, Krombach, Fritz, additional, Holdt, Lesca, additional, Brandau, Sven, additional, Vogl, Thomas, additional, Lauber, Kirsten, additional, Uhl, Bernd, additional, and Reichel, Christoph A, additional

Published
2021
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12. Stab Injury of the Petrosal Bone: Case Report and Literature Review.

Author

Högerle, Catalina, Nörenberg, Dominik, Biczok, Annamaria, Kunz, Mathias, Baumeister, Philipp, and Uhl, Bernd

Subjects
KNIVES, PETROUS bone, PENETRATING wounds, ANESTHESIOLOGISTS, OPERATIVE otolaryngology, NEUROSURGERY, TERTIARY care, MAGNETIC resonance imaging, HEALTH care teams, GLASGOW Coma Scale, COMPUTED tomography, HEAD injuries
Abstract

Penetrating traumas of the head are generally life-threatening injuries, whose management poses a substantial challenge for emergency department teams. These injuries are characteristically violence-associated and frequently accompanied by damage of essential organs including brain, meninges, large vessels, cranial nerves, eyes, viscerocranium, internal ear, and/or labyrinth. Here, we present an exceptional case of head trauma caused by a knife blade, which was stuck deep inside in the petrous bone. After the extraction of the knife, the patient had very few immediate and no long-term post-traumatic complications. In conclusion, high-end technical equipment as well as an interdisciplinary team of specialized physicians is recommended for the management of penetrating head trauma to optimize the outcome. [ABSTRACT FROM AUTHOR]

Published
2022
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14. uPA‐PAI‐1 heteromerization promotes breast cancer progression by attracting tumorigenic neutrophils

Author

Uhl, Bernd, A Mittmann, Laura, Dominik, Julian, Hennel, Roman, Smiljanov, Bojan, Haring, Florian, B Schaubächer, Johanna, Braun, Constanze, Padovan, Lena, Pick, Robert, Canis, Martin, Schulz, Christian, Mack, Matthias, Gutjahr, Ewgenija, Sinn, Peter, Heil, Jörg, Steiger, Katja, Kanse, Sandip M, Weichert, Wilko, Sperandio, Markus, Lauber, Kirsten, Krombach, Fritz, and Reichel, Christoph A

Subjects
Medicine (General), Vascular Biology & Angiogenesis, Immunology, Breast Neoplasms, Articles, QH426-470, Urokinase-Type Plasminogen Activator, Article, breast cancer, R5-920, neutrophils, Lymphatic Metastasis, Plasminogen Activator Inhibitor 1, Genetics, Humans, biomarker, Female, fibrinolysis, innate immunity, Cancer
Abstract

High intratumoral levels of urokinase‐type plasminogen activator (uPA)‐plasminogen activator inhibitor‐1 (PAI‐1) heteromers predict impaired survival and treatment response in early breast cancer. The pathogenetic role of this protein complex remains obscure. Here, we demonstrate that heteromerization of uPA and PAI‐1 multiplies the potential of the single proteins to attract pro‐tumorigenic neutrophils. To this end, tumor‐released uPA‐PAI‐1 utilizes very low‐density lipoprotein receptor and mitogen‐activated protein kinases to initiate a pro‐inflammatory program in perivascular macrophages. This enforces neutrophil trafficking to cancerous lesions and skews these immune cells toward a pro‐tumorigenic phenotype, thus supporting tumor growth and metastasis. Blockade of uPA‐PAI‐1 heteromerization by a novel small‐molecule inhibitor interfered with these events and effectively prevented tumor progression. Our findings identify a therapeutically targetable, hitherto unknown interplay between hemostasis and innate immunity that drives breast cancer progression. As a personalized immunotherapeutic strategy, blockade of uPA‐PAI‐1 heteromerization might be particularly beneficial for patients with highly aggressive uPA‐PAI‐1high tumors., Uhl et al report that heteromerization of the serine protease urokinase‐type plasminogen activator (uPA) and the serpin plasminogen activator inhibitor‐1 (PAI‐1) enforces the trafficking of pro‐tumorigenic neutrophils to malignant lesions in highly aggressive subtypes of breast cancer.

Published
2021

15. Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

Author

Immler, Roland, Lange-Sperandio, Bärbel, Steffen, Tobias, Beck, Heike, Rohwedder, Ina, Roth, Jonas, Napoli, Matteo, Hupel, Georg, Pfister, Frederik, Popper, Bastian, Uhl, Bernd, Mannell, Hanna, Reichel, Christoph A., Vielhauer, Volker, Scherberich, Jürgen, Sperandio, Markus, and Pruenster, Monika

Subjects
Inflammation, Male, uromodulin, kidney disease, Immunology, leukocyte recruitment, Polymerization, Mice, Inbred C57BL, Human Umbilical Vein Endothelial Cells, Leukocytes, Animals, Humans, Female, Kidney Diseases, damage associated molecular pattern (DAMP), Cell Adhesion Molecules, Cells, Cultured, Original Research, Abdominal Muscles
Abstract

Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.

Published
2020

17. Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90

Author

Ernst, Anne, Hennel, Roman, Krombach, Julia, Kapfhammer, Heidi, Brix, Nikko, Zuchtriegel, Gabriele, Uhl, Bernd, Reichel, Christoph A., Frey, Benjamin, Gaipl, Udo S., Winssinger, Nicolas, Shirasawa, Senji, Sasazuki, Takehiko, Sperandio, Markus, Belka, Claus, and Lauber, Kirsten

Subjects
Cancer Research, DAMPs, secondary necrosis, Oncology, Medizinische Fakultät, immune priming, HSP90 inhibition, colorectal cancer, ddc:610, anti-tumor immunity, cancer immunology, radiotherapy, Original Research
Abstract

Radiotherapy is an essential part of multi-modal cancer therapy. Nevertheless, for certain cancer entities such as colorectal cancer (CRC) the indications of radiotherapy are limited due to anatomical peculiarities and high radiosensitivity of the surrounding normal tissue. The development of molecularly targeted, combined modality approaches may help to overcome these limitations. Preferably, such strategies should not only enhance radiation-induced tumor cell killing and the abrogation of tumor cell clonogenicity, but should also support the stimulation of anti-tumor immune mechanisms – a phenomenon which moved into the center of interest of preclinical and clinical research in radiation oncology within the last decade. The present study focuses on inhibition of heat shock protein 90 (HSP90) whose combination with radiotherapy has previously been reported to exhibit convincing therapeutic synergism in different preclinical cancer models. By employing in vitro and in vivo analyses, we examined if this therapeutic synergism also applies to the priming of anti-tumor immune mechanisms in model systems of CRC. Our results indicate that the combination of HSP90 inhibitor treatment and ionizing irradiation induced apoptosis in colorectal cancer cells with accelerated transit into secondary necrosis in a hyperactive Kras-dependent manner. During secondary necrosis, dying cancer cells released different classes of damage-associated molecular patterns (DAMPs) that stimulated migration and recruitment of monocytic cells in vitro and in vivo. Additionally, these dying cancer cell-derived DAMPs enforced the differentiation of a monocyte-derived antigen presenting cell (APC) phenotype which potently triggered the priming of allogeneic T cell responses in vitro. In summary, HSP90 inhibition – apart from its radiosensitizing potential – obviously enables and supports the initial steps of anti-tumor immune priming upon radiotherapy and thus represents a promising partner for combined modality approaches. The therapeutic performance of such strategies requires further in-depth analyses, especially for but not only limited to CRC.

Published
2020

21. Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis

Author

Liu, Xiao, primary, Li, Junjian, additional, Cadilha, Bruno Loureiro, additional, Markota, Anamarija, additional, Voigt, Cornelia, additional, Huang, Zhe, additional, Lin, Peter P., additional, Wang, Daisy D., additional, Dai, Juncheng, additional, Kranz, Gisela, additional, Krandick, Anna, additional, Libl, Darko, additional, Zitzelsberger, Horst, additional, Zagorski, Isabella, additional, Braselmann, Herbert, additional, Pan, Min, additional, Zhu, Sibo, additional, Huang, Yuanchi, additional, Niedermeyer, Sebastian, additional, Reichel, Christoph A., additional, Uhl, Bernd, additional, Briukhovetska, Daria, additional, Suárez, Javier, additional, Kobold, Sebastian, additional, Gires, Olivier, additional, and Wang, Hongxia, additional

Published
2019
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23. Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia–Reperfusion

Author

Praetner, Marc, primary, Zuchtriegel, Gabriele, additional, Holzer, Martin, additional, Uhl, Bernd, additional, Schaubächer, Johanna, additional, Mittmann, Laura, additional, Fabritius, Matthias, additional, Fürst, Robert, additional, Zahler, Stefan, additional, Funken, Dominik, additional, Lerchenberger, Maximilian, additional, Khandoga, Andrej, additional, Kanse, Sandip, additional, Lauber, Kirsten, additional, Krombach, Fritz, additional, and Reichel, Christoph A., additional

Published
2018
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25. Thrombozyten leiten Leukozyten zum Ort der Entzündung

Author

Reichel, Christoph, Zuchtriegel, Gabriele, Uhl, Bernd, Puhr-Westerheide, Daniel, Pörnbacher, Michaela, Lauber, Kirsten, and Krombach, Fritz

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Einleitung: Die Rekrutierung von Immunzellen zum Ort der Infektion oder Gewebeschädigung ist grundlegender Bestandteil von Entzündungsreaktionen. Wie zirkulierende Leukozyten eine geeignete Stelle für die Auswanderung aus dem Gefäßsystem in das Gewebe finden ist größtenteils[zum vollständigen Text gelangen Sie über die oben angegebene URL], 87. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie

Published
2016

27. Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium

Author

Kirsch, Julian, primary, Schneider, Holger, additional, Pagel, Judith-Irina, additional, Rehberg, Markus, additional, Singer, Miriam, additional, Hellfritsch, Juliane, additional, Chillo, Omary, additional, Schubert, Kai Michael, additional, Qiu, Jiehua, additional, Pogoda, Kristin, additional, Kameritsch, Petra, additional, Uhl, Bernd, additional, Pircher, Joachim, additional, Deindl, Elisabeth, additional, Müller, Susanna, additional, Kirchner, Thomas, additional, Pohl, Ulrich, additional, Conrad, Marcus, additional, and Beck, Heike, additional

Published
2016
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30. Tissue Plasminogen Activator Promotes Postischemic Neutrophil Recruitment via Its Proteolytic and Nonproteolytic Properties

Author

Uhl, Bernd, primary, Zuchtriegel, Gabriele, additional, Puhr-Westerheide, Daniel, additional, Praetner, Marc, additional, Rehberg, Markus, additional, Fabritius, Matthias, additional, Hessenauer, Maximilian, additional, Holzer, Martin, additional, Khandoga, Andrej, additional, Fürst, Robert, additional, Zahler, Stefan, additional, Krombach, Fritz, additional, and Reichel, Christoph A., additional

Published
2014
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31. Endogenous and exogenous pentraxin-3 limits postischemic acute and chronic kidney injury

Author

Lech, Maciej, primary, Römmele, Christoph, additional, Gröbmayr, Regina, additional, Eka Susanti, Heni, additional, Kulkarni, Onkar P., additional, Wang, Shijun, additional, Gröne, Hermann-Josef, additional, Uhl, Bernd, additional, Reichel, Christoph, additional, Krombach, Fritz, additional, Garlanda, Cecilia, additional, Mantovani, Alberto, additional, and Anders, Hans-Joachim, additional

Published
2013
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32. Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4

Author

Allam, Ramanjaneyulu, primary, Scherbaum, Christina Rebecca, additional, Darisipudi, Murthy Narayana, additional, Mulay, Shrikant R., additional, Hägele, Holger, additional, Lichtnekert, Julia, additional, Hagemann, Jan Henrik, additional, Rupanagudi, Khader Valli, additional, Ryu, Mi, additional, Schwarzenberger, Claudia, additional, Hohenstein, Bernd, additional, Hugo, Christian, additional, Uhl, Bernd, additional, Reichel, Christoph A., additional, Krombach, Fritz, additional, Monestier, Marc, additional, Liapis, Helen, additional, Moreth, Kristin, additional, Schaefer, Liliana, additional, and Anders, Hans-Joachim, additional

Published
2012
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33. Urokinase-Type Plasminogen Activator Promotes Paracellular Transmigration of Neutrophils Via Mac-1, But Independently of Urokinase-Type Plasminogen Activator Receptor

Author

Reichel, Christoph A., primary, Uhl, Bernd, additional, Lerchenberger, Max, additional, Puhr-Westerheide, Daniel, additional, Rehberg, Markus, additional, Liebl, Johanna, additional, Khandoga, Andrej, additional, Schmalix, Wolfgang, additional, Zahler, Stefan, additional, Deindl, Elisabeth, additional, Lorenzl, Stefan, additional, Declerck, Paul J., additional, Kanse, Sandip, additional, and Krombach, Fritz, additional

Published
2011
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35. Stab Injury of the Petrosal Bone: Case Report and Literature Review.

Author

Högerle C, Nörenberg D, Biczok A, Kunz M, Baumeister P, and Uhl B

Subjects
Humans, Petrous Bone diagnostic imaging, Skull, Wounds, Stab complications, Wounds, Stab surgery, Head Injuries, Penetrating complications, Craniocerebral Trauma complications
Abstract

Penetrating traumas of the head are generally life-threatening injuries, whose management poses a substantial challenge for emergency department teams. These injuries are characteristically violence-associated and frequently accompanied by damage of essential organs including brain, meninges, large vessels, cranial nerves, eyes, viscerocranium, internal ear, and/or labyrinth. Here, we present an exceptional case of head trauma caused by a knife blade, which was stuck deep inside in the petrous bone. After the extraction of the knife, the patient had very few immediate and no long-term post-traumatic complications. In conclusion, high-end technical equipment as well as an interdisciplinary team of specialized physicians is recommended for the management of penetrating head trauma to optimize the outcome.

Published
2022
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36. Vitronectin stabilizes intravascular adhesion of neutrophils by coordinating β2 integrin clustering.

Author

Zuchtriegel G, Uhl B, Pick R, Ramsauer M, Dominik J, Mittmann LA, Canis M, Kanse S, Sperandio M, Krombach F, and Reichel CA

Subjects
Animals, Cell Adhesion, Cluster Analysis, Endothelial Cells, Mice, Neutrophils, CD18 Antigens, Vitronectin
Abstract

The recruitment of neutrophils from the microvasculature to the site of injury or infection represents a key event in the inflammatory response. Vitronectin (VN) is a multifunctional macromolecule abundantly present in blood and extracellular matrix. The role of this glycoprotein in the extravasation process of circulating neutrophils remains elusive. Employing advanced in vivo/ex vivo imaging techniques in different mouse models as well as in vitro methods, we uncovered a previously unrecognized function of VN in the transition of dynamic to static intravascular interactions of neutrophils with microvascular endothelial cells. These distinct properties of VN require the heteromerization of this glycoprotein with plasminogen activator inhibitor-1 (PAI- 1) on the activated venular endothelium and subsequent interactions of this protein complex with the scavenger receptor low-density lipoprotein receptor-related protein-1 on intravascularly adhering neutrophils. This induces p38 mitogen-activated protein kinases-dependent intracellular signaling events which, in turn, regulates the proper clustering of the b2 integrin lymphocyte function associated antigen-1 on the surface of these immune cells. As a consequence of this molecular interplay, neutrophils become able to stabilize their adhesion to the microvascular endothelium and, subsequently, to extravasate to the perivascular tissue. Hence, endothelial-bound VN-PAI-1 heteromers stabilize intravascular adhesion of neutrophils by coordinating b2 integrin clustering on the surface of these immune cells, thereby effectively controlling neutrophil trafficking to inflamed tissue. Targeting this protein complex might be beneficial for the prevention and treatment of inflammatory pathologies.

Published
2021
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