79 results on '"Christoph Scheiermann"'
Search Results
2. Binding of Rap1 and Riam to Talin1 Fine-Tune β2 Integrin Activity During Leukocyte Trafficking
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Thomas Bromberger, Sarah Klapproth, Ina Rohwedder, Jasmin Weber, Robert Pick, Laura Mittmann, Soo Jin Min-Weißenhorn, Christoph A. Reichel, Christoph Scheiermann, Markus Sperandio, and Markus Moser
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talin ,Riam ,Rap1 ,leukocyte adhesion ,leukocyte rolling ,integrin activation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
β2 integrins mediate key processes during leukocyte trafficking. Upon leukocyte activation, the structurally bent β2 integrins change their conformation towards an extended, intermediate and eventually high affinity conformation, which mediate slow leukocyte rolling and firm arrest, respectively. Translocation of talin1 to integrin adhesion sites by interactions with the small GTPase Rap1 and the Rap1 effector Riam precede these processes. Using Rap1 binding mutant talin1 and Riam deficient mice we show a strong Riam-dependent T cell homing process to lymph nodes in adoptive transfer experiments and by intravital microscopy. Moreover, neutrophils from compound mutant mice exhibit strongly increased rolling velocities to inflamed cremaster muscle venules compared to single mutants. Using Hoxb8 cell derived neutrophils generated from the mutant mouse strains, we show that both pathways regulate leukocyte rolling and adhesion synergistically by inducing conformational changes of the β2 integrin ectodomain. Importantly, a simultaneous loss of both pathways results in a rolling phenotype similar to talin1 deficient neutrophils suggesting that β2 integrin regulation primarily occurs via these two pathways.
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- 2021
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3. Editorial: Circadian Control of Immunity
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Koichi Ikuta and Christoph Scheiermann
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circadian immunity ,innate immunity ,adaptive immunity ,leukocyte migration ,control of circadian immunity ,Immunologic diseases. Allergy ,RC581-607 - Published
- 2020
- Full Text
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4. Control of Leukocyte Trafficking by Stress-Associated Hormones
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Louise M. Ince, Jasmin Weber, and Christoph Scheiermann
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catecholamine ,glucocorticoid ,adrenergic signaling ,neutrophil ,lymphocyte ,circadian rhythm ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Leukocyte migration is a crucial process in both homeostatic and inflammatory conditions. The spatiotemporal distribution of immune cells is balanced between processes of cellular mobilization into the bloodstream, their adhesion to vascular beds and trafficking into tissues. Systemic regulation of leukocyte mobility is achieved by different signals including neuronal and hormonal cues, of which the catecholamines and glucocorticoids have been most extensively studied. These hormones are often associated with a stress response, however they regulate immune cell trafficking also in steady state, with effects dependent upon cell type, location, time-of-day, concentration, and duration of signal. Systemic administration of catecholamines, such as the sympathetic neurotransmitters adrenaline and noradrenaline, increases neutrophil numbers in the bloodstream but has different effects on other leukocyte populations. In contrast, local, endogenous sympathetic tone has been shown to be crucial for dynamic daily changes in adhesion molecule expression in the bone marrow and skeletal muscle, acting as a key signal to the endothelium and stromal cells to regulate immune cell trafficking. Conversely, glucocorticoids are often reported as anti-inflammatory, although recent data shows a more complex role, particularly under steady-state conditions. Endogenous changes in circulating glucocorticoid concentration induce redistribution of cells and potentiate inflammatory responses, and in many paradigms glucocorticoid action is strongly influenced by time of day. In this review, we discuss the current knowledge of catecholamine and glucocorticoid regulation of leukocyte migration under homeostatic and stimulated conditions.
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- 2019
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5. Differential requirement of kindlin-3 for T cell progenitor homing to the non-vascularized and vascularized thymus
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Federico Andrea Moretti, Sarah Klapproth, Raphael Ruppert, Andreas Margraf, Jasmin Weber, Robert Pick, Christoph Scheiermann, Markus Sperandio, Reinhard Fässler, and Markus Moser
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kindlin-3 ,integrin ,T cell homing ,thymus development ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The role of integrin-mediated adhesion during T cell progenitor homing to and differentiation within the thymus is ill-defined, mainly due to functional overlap. To circumvent compensation, we disrupted the hematopoietic integrin regulator kindlin-3 in mice and found a progressive thymus atrophy that is primarily caused by an impaired homing capacity of T cell progenitors to the vascularized thymus. Notably, the low shear flow conditions in the vascular system at midgestation allow kindlin-3-deficient fetal liver-derived T cell progenitors to extravasate via pharyngeal vessels and colonize the avascular thymus primordium. Once in the thymus, kindlin-3 promotes intrathymic T cell proliferation by facilitating the integrin-dependent crosstalk with thymic antigen presenting cells, while intrathymic T cell migration, maturation into single positive CD4 and CD8 T cells and release into the circulation proceed without kindlin-3. Thus, kindlin-3 is dispensable for integrin-mediated T cell progenitor adhesion and signalling at low and indispensable at high shear forces.
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- 2018
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6. Control of lymph node activity by direct local innervation
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Francesco De Virgiliis, Valeria Maria Oliva, Burak Kizil, and Christoph Scheiermann
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Neurotransmitter Agents ,Calcitonin Gene-Related Peptide ,General Neuroscience ,Neuropeptides ,Humans ,Lymph Nodes ,Substance P - Abstract
The nervous system detects environmental and internal stimuli and relays this information to immune cells via neurotransmitters and neuropeptides. This is essential to respond appropriately to immunogenic threats and to support system homeostasis. Lymph nodes (LNs) act as sentinels where adaptive immune responses are generated. They are richly innervated by peripheral sympathetic and sensory nerves, which are responsible for the local secretion of neurotransmitters by sympathetic fibers, such as norepinephrine, and neuropeptides by sensory fibers, including calcitonin gene-related peptide (CGRP) and substance P. Additionally, time-of-day-dependent oscillations in nerve activity are associated with differential immune responses, suggesting a potential role for neuroimmune interactions in coordinating immunity in a circadian fashion. Here, we discuss how LN activity is controlled by local innervation.
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- 2022
7. Supplementary Table 1 from MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell–Suppressive Functions
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Stéphanie Hugues, Melody A. Swartz, Christoph Scheiermann, Robert Pick, Ludovic J. Wrobel, Dale Brighouse, Guillaume Harlé, Julien Angelillo, Juan Dubrot, Laure Garnier, and Anastasia O. Gkountidi
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Supplementary Table 1
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- 2023
8. Data from MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell–Suppressive Functions
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Stéphanie Hugues, Melody A. Swartz, Christoph Scheiermann, Robert Pick, Ludovic J. Wrobel, Dale Brighouse, Guillaume Harlé, Julien Angelillo, Juan Dubrot, Laure Garnier, and Anastasia O. Gkountidi
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Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment (TME). Here, we have investigated the ability of tumoral lymphatic endothelial cells (LEC) to function as MHC class II–restricted antigen-presenting cells in the regulation of antitumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we have shown that tumoral LECs upregulate MHC class II and the MHC class II antigen-processing machinery, and that they promote regulatory T-cell (Treg) expansion ex vivo. In mice with LEC-restricted lack of MHC class II expression, tumor growth was severely impaired, whereas tumor-infiltrating effector T cells were increased. Reduction of tumor growth and reinvigoration of tumor-specific T-cell responses both resulted from alterations of the tumor-infiltrating Treg transcriptome and phenotype. Treg-suppressive functions were profoundly altered in tumors lacking MHC class II in LECs. No difference in effector T-cell responses or Treg phenotype and functions was observed in tumor-draining lymph nodes, indicating that MHC class II–restricted antigen presentation by LECs was required locally in the TME to confer potent suppressive functions to Tregs. Altogether, our study suggests that MHC class II–restricted antigen-presenting tumoral LECs function as a local brake, dampening T cell–mediated antitumor immunity and promoting intratumoral Treg-suppressive functions.
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- 2023
9. Supplementary Figures 1-12 from MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell–Suppressive Functions
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Stéphanie Hugues, Melody A. Swartz, Christoph Scheiermann, Robert Pick, Ludovic J. Wrobel, Dale Brighouse, Guillaume Harlé, Julien Angelillo, Juan Dubrot, Laure Garnier, and Anastasia O. Gkountidi
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Supplementary Figures and Legends
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- 2023
10. Dendritic cells direct circadian anti-tumor immune responses
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Chen Wang, Coline Barnoud, Mara Cenerenti, Mengzhu Sun, Irene Caffa, Burak Kizil, Ruben Bill, Yuanlong Liu, Robert Pick, Laure Garnier, Olga A. Gkountidi, Louise M. Ince, Stephan Holtkamp, Nadine Fournier, Olivier Michielin, Daniel E. Speiser, Stéphanie Hugues, Alessio Nencioni, Mikaël J. Pittet, Camilla Jandus, and Christoph Scheiermann
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Multidisciplinary ,610 Medicine & health - Abstract
The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.
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- 2023
11. The circadian immune system
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Chen Wang, Lydia K. Lutes, Christoph Scheiermann, and Coline Barnoud
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Immune System ,Immunology ,General Medicine ,Circadian Rhythm - Abstract
The immune system is highly time-of-day dependent. Pioneering studies in the 1960s were the first to identify immune responses to be under a circadian control. Only in the last decade, however, have the molecular factors governing circadian immune rhythms been identified. These studies have revealed a highly complex picture of the interconnectivity of rhythmicity within immune cells with that of their environment. Here, we provide a global overview of the circadian immune system, focusing on recent advances in the rapidly expanding field of circadian immunology.
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- 2022
12. Plasmacytoid dendritic cells regulate megakaryocyte and platelet homeostasis
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Florian Gaertner, Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Chenglong Guo, Jutta Weitz, Anne Dueck, Zhe Zhang, Dominic van den Heuvel, Valeria Fumagalli, Michael Lorenz, Louisa von Baumgarten, Konstantin Stark, Tobias Straub, Saskia von Stillfried, Peter Boor, Marco Colonna, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, Stefan Engelhardt, William C. Aird, Tobias Petzold, Michael Sixt, Martina Rudelius, Claus Nerlov, Matteo Iannacone, Robert A. J. Oostendorp, and Steffen Massberg
- Abstract
Platelet homeostasis is essential for vascular integrity and immune defense. While the process of platelet formation by fragmenting megakaryocytes (thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of megakaryocytes by their progenitor cells (megakaryopoiesis) remains unclear. Here we use intravital 2 photon microscopy to track individual megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as crucial bone marrow niche cells that regulate megakaryopoiesis. pDCs monitor the bone marrow for platelet-producing megakaryocytes and deliver IFN-α to the megakaryocytic niche to trigger local on-demand proliferation of megakaryocyte progenitors. This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for megakaryocyte and platelet homeostasis in steady state and stress. However, uncontrolled pDC function within the megakaryocytic niche is detrimental. Accordingly, we show that pDCs activated by SARS-CoV2 drive inappropriate megakaryopoiesis associated with thrombotic complications. Together, we uncover a hitherto unknown megakaryocytic bone marrow niche maintained by the constitutive delivery of pDC-derived IFN-α.
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- 2022
13. Dendritic Cells Direct Circadian Anti‐Tumor Immune Response
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Chen Wang, Coline Barnoud, Burak Kizil, and Christoph Scheiermann
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
14. Benefit of Circadian Clocks in Adaptive Immunity And Vaccination Responses
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Coline Barnoud, Louise M. Ince, Lydia K. Lutes, Robert Pick, Chen Wang, Stéphane Jemelin, and Christoph Scheiermann
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
15. Time‐of‐Day Influence on Central Nervous System Autoimmunity
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Coline Barnoud, Chen Wang, Louise M. Ince, and Christoph Scheiermann
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
16. Peripheral neurotransmitters in the immune system
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Coline Barnoud, Chien-Sin Chen, and Christoph Scheiermann
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0301 basic medicine ,Nervous system ,Physiology ,business.industry ,Substance P ,biochemical phenomena, metabolism, and nutrition ,03 medical and health sciences ,chemistry.chemical_compound ,Norepinephrine ,030104 developmental biology ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,chemistry ,Immunity ,Dopamine ,Physiology (medical) ,Peripheral nervous system ,medicine ,bacteria ,business ,Neuroscience ,030217 neurology & neurosurgery ,Acetylcholine ,medicine.drug - Abstract
The nervous system exerts potent control over the immune system. A wealth of recent data strongly implicate different branches of the peripheral nervous system in toning immunity, including the sympathetic and parasympathetic as well as the sensory nervous system. Neurotransmitters released by peripheral nerves mediate the interactions with the immune system, which can have pro-or anti-inflammatory effects. In this review, we focus on these recent developments by discussing the effects of norepinephrine, acetylcholine, VIP, NMU, CGRP, substance P as well as dopamine on immune cells.
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- 2021
17. Loss of direct adrenergic innervation after peripheral nerve injury causes lymph node expansion through IFN-γ
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Barbara U. Schraml, Christoph Scheiermann, Coline Barnoud, Elisabeth Deindl, Sophia Martina Hergenhan, Johanna Salvermoser, Manuel Lasch, Stephan Holtkamp, Alba de Juan, Burak Kizil, Louise Ince, Jasmin Weber, Chien-Sin Chen, Chen Wang, Lydia Lutes, and Dirk Baumjohann
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Immunology ,Adrenergic ,Autoimmunity ,CD8-Positive T-Lymphocytes ,ddc:616.07 ,Peripheral Nerve Injuries / pathology ,Article ,Inflammation / pathology ,Interferon-gamma ,03 medical and health sciences ,Adrenergic Agents ,0302 clinical medicine ,Immune system ,Neuroinflammation ,Peripheral Nerve Injuries ,Antigens / immunology ,Animals ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Antigens ,Lymph node ,Inflammation ,Denervation ,business.industry ,Axotomy ,Lymph Nodes / pathology ,Sciatic Nerve ,Interferon-gamma / metabolism ,Mice, Inbred C57BL ,Sciatic Nerve / pathology ,CD8-Positive T-Lymphocytes / immunology ,030104 developmental biology ,medicine.anatomical_structure ,Peripheral nerve injury ,Lymph Nodes ,Sciatic nerve ,business ,Sciatic Nerve / immunology ,030217 neurology & neurosurgery ,Adrenergic Agents / metabolism ,Signal Transduction ,Sensory nerve - Abstract
This study shows loss of sympathetic innervation to the popliteal lymph node to induce IFN-γ expression in CD8 T cells, causing expansion. This is rescued by β2 adrenergic receptor agonists, demonstrating the pro-inflammatory effect of loss of direct adrenergic input., Peripheral nerve injury can cause debilitating disease and immune cell–mediated destruction of the affected nerve. While the focus has been on the nerve-regenerative response, the effect of loss of innervation on lymph node function is unclear. Here, we show that the popliteal lymph node (popLN) receives direct neural input from the sciatic nerve and that sciatic denervation causes lymph node expansion. Loss of sympathetic, adrenergic tone induces the expression of IFN-γ in LN CD8 T cells, which is responsible for LN expansion. Surgery-induced IFN-γ expression and expansion can be rescued by β2 adrenergic receptor agonists but not sensory nerve agonists. These data demonstrate the mechanisms governing the pro-inflammatory effect of loss of direct adrenergic input on lymph node function.
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- 2021
18. Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity
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Christoph Scheiermann, Jennifer Niven, Stéphanie Hugues, Gaëlle Clavel, Monique Gannagé, Juan Dubrot, Natacha Bessis, Guillaume Harlé, Camille Kowalski, Dale Brighouse, and Robert Pick
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0301 basic medicine ,Naive T cell ,Regulatory T cell ,T cell ,Immunology ,Cell ,Population ,Antigen presentation ,Cellular homeostasis ,chemical and pharmacologic phenomena ,Autoimmunity ,ddc:616.07 ,T-Lymphocytes, Regulatory ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Sphingosine ,Macroautophagy ,Immune Tolerance ,medicine ,Animals ,Humans ,Immunology and Allergy ,education ,Cells, Cultured ,Lymphatic Vessels ,Inflammation ,education.field_of_study ,Chemistry ,Arthritis ,fungi ,Autophagy ,Endothelial Cells ,hemic and immune systems ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Th17 Cells ,Lymph Nodes ,sense organs ,Lysophospholipids ,Tolerance - Abstract
The authors show that autophagy in lymphatic endothelial cells (LECs) dampens collagen-induced arthritis by regulating two distinct pathways: the promotion of T reg cells in LNs and the inhibition of S1P-dependent migration of pathogenic Th17 cells in inflamed organs., Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.
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- 2021
19. Ex Vivo Whole-Mount Imaging of Leukocyte Migration to the Bone Marrow
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Stephan Holtkamp and Christoph Scheiermann
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0301 basic medicine ,Whole mount ,Leukocyte migration ,Pathology ,medicine.medical_specialty ,Adoptive cell transfer ,Stromal cell ,Hematopoietic organ ,Biology ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Bone marrow ,Ex vivo - Abstract
The bone marrow is the major hematopoietic organ, consisting of distinct microenvironmental niches for the production of hematopoietic cells. Advanced visualizing methods are required to define and better understand the interactions between stromal and hematopoietic cells. In this chapter, we describe an ex vivo whole-mount imaging technique of the bone marrow, which allows for a fast, high-quality, and three-dimensional visualization of different bone marrow components. We provide a guide for conducting adoptive transfer experiments of fluorescently labeled leukocytes and visualizing their location in the bone marrow with respect to the bone marrow vasculature. This method presents a quick, easy, and inexpensive approach to image the bone marrow in three dimensions.
- Published
- 2021
20. MHC class II antigen presentation by lymphatic endothelial cells in tumors promotes intratumoral regulatory T cell-suppressive functions
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Anastasia O, Gkountidi, Laure, Garnier, Juan, Dubrot, Julien, Angelillo, Guillaume, Harlé, Dale, Brighouse, Ludovic J, Wrobel, Robert, Pick, Christoph, Scheiermann, Melody A, Swartz, and Stéphanie, Hugues
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ddc:616 ,Antigen Presentation ,Primary Cell Culture ,Histocompatibility Antigens Class II ,Endothelial Cells ,chemical and pharmacologic phenomena ,Cell Communication ,ddc:616.07 ,T-Lymphocytes, Regulatory ,Coculture Techniques ,Disease Models, Animal ,Mice ,Neoplasms ,Tumor Cells, Cultured ,Tumor Microenvironment ,Animals ,Humans ,Female ,Tumor Escape ,Lymph Nodes ,sense organs ,Lymphatic Vessels - Abstract
Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment (TME). Here, we have investigated the ability of tumoral lymphatic endothelial cells (LEC) to function as MHC class II-restricted antigen-presenting cells in the regulation of antitumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we have shown that tumoral LECs upregulate MHC class II and the MHC class II antigen-processing machinery, and that they promote regulatory T-cell (Treg) expansion ex vivo In mice with LEC-restricted lack of MHC class II expression, tumor growth was severely impaired, whereas tumor-infiltrating effector T cells were increased. Reduction of tumor growth and reinvigoration of tumor-specific T-cell responses both resulted from alterations of the tumor-infiltrating Treg transcriptome and phenotype. Treg-suppressive functions were profoundly altered in tumors lacking MHC class II in LECs. No difference in effector T-cell responses or Treg phenotype and functions was observed in tumor-draining lymph nodes, indicating that MHC class II-restricted antigen presentation by LECs was required locally in the TME to confer potent suppressive functions to Tregs. Altogether, our study suggests that MHC class II-restricted antigen-presenting tumoral LECs function as a local brake, dampening T cell-mediated antitumor immunity and promoting intratumoral Treg-suppressive functions.
- Published
- 2021
21. Circadian clocks guide dendritic cells into skin lymphatics
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Violetta Pilorz, Chien-Sin Chen, Robert Pick, Julia Philippou-Massier, Leonie Holtermann, Dietmar Vestweber, Barbara U. Schraml, David Laubender, Coline Barnoud, Madeleine T. Schmitt, Louise Ince, Jörg Renkawitz, Stephan Holtkamp, Charna Dibner, Flore Sinturel, Henrik Oster, Michael Mühlstädt, Wolf-Henning Boehncke, Markus Sperandio, Stephane Jemelin, Cornelia Halin, Jasmin Weber, and Christoph Scheiermann
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Male ,Chemokine ,Cell type ,Time Factors ,Letter ,Adaptive immunity ,Immunology ,Circadian clock ,Mice, Transgenic ,chemical and pharmacologic phenomena ,ddc:616.07 ,ddc:590 ,Circadian Clocks ,Leukocyte Trafficking ,Animals ,Humans ,Immunology and Allergy ,Circadian rhythm ,ddc:610 ,ddc:612 ,Cells, Cultured ,Aged ,Skin ,Chemokine CCL21 ,biology ,integumentary system ,Circadian Rhythm Signaling Peptides and Proteins ,Chemotaxis ,hemic and immune systems ,Dendritic Cells ,Acquired immune system ,Cell biology ,Mice, Inbred C57BL ,Lymphatic system ,Lymphatic vessels ,biology.protein ,Female ,Lymph Nodes ,Cell Adhesion Molecules ,CCL21 - Abstract
Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies., Scheiermann and colleagues show that circadian clocks control the infiltration of dendritic cells into skin lymphatics in mice and humans, with a peak migration to the lymph nodes during the rest phase.
- Published
- 2021
22. Paul S. Frenette (1965–2021)
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Daniel Lucas, Andrés Hidalgo, Sandra Pinho, and Christoph Scheiermann
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Philosophy ,Art history ,Cell Biology ,ddc:616.07 ,Cell biology - Published
- 2021
23. Timing vaccination against SARS-CoV-2
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Coline Barnoud, Chen Wang, and Christoph Scheiermann
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Cell division ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,Vaccination ,COVID-19 ,Autoimmunity ,Cell Biology ,ddc:616.07 ,Biology ,Research Highlight ,Virology ,Humans ,Circadian rhythms ,Letter to the Editor ,Molecular Biology - Published
- 2021
24. Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis
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Alexandra Baecklund, Hong Jin, Philipp Müller, Oliver Soehnlein, Peter Libby, Christian Weber, W.E. Kempf, Michael Hristov, Chien-Sin Chen, Philip Wenzel, Michael Molitor, Markus Krane, Matthias Nahrendorf, Lars Maegdefessel, Anna-Sophia Zimmermann, Karl-Heinz Ladwig, Christoph Scheiermann, Anna-Lena Steinsiek, Julia Hinterdobler, Jana Wobst, Almut Meesmann, Thorsten Kessler, Hendrik B. Sager, Quinte Braster, Aldo Moggio, Maarten Hulsmans, Ingo Hilgendorf, Baiba Vilne, Carina Mauersberger, Simin Schott, Heribert Schunkert, Biochemie, and RS: Carim - B01 Blood proteins & engineering
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0301 basic medicine ,Chemokine ,Sympathetic nervous system ,SUBSETS ,Adhesion (medicine) ,ddc:616.07 ,030204 cardiovascular system & hematology ,Acute mental stress ,Neuroimmune interaction ,Mice ,0302 clinical medicine ,Mental stress ,AcademicSubjects/MED00200 ,MACROPHAGES ,Vascular inflammation ,Mice, Knockout ,biology ,TRIGGERS ,Plaque, Atherosclerotic ,ddc ,medicine.anatomical_structure ,CARDIOVASCULAR-DISEASE ,MONOCYTES ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,medicine.drug ,ACUTE MYOCARDIAL-INFARCTION ,STEADY-STATE ,Leucocyte recruitment ,Inflammation ,HEMATOPOIESIS ,MECHANISMS ,Norepinephrine (medication) ,03 medical and health sciences ,Translational Research ,medicine ,Animals ,Humans ,TRAFFICKING ,Lung ,business.industry ,Endothelial Cells ,medicine.disease ,Atherosclerosis ,Thrombosis and Antithrombotic Treatment ,Mice, Inbred C57BL ,Acute Mental Stress ,Leucocyte Recruitment ,Neuroimmune Interaction ,Sympathetic Nervous System ,Vascular Inflammation ,Disease Models, Animal ,030104 developmental biology ,Atheroma ,Immunology ,biology.protein ,Endothelium, Vascular ,business ,Stress, Psychological - Abstract
Aims Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear. Methods and results Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques. Conclusion Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability., Graphical Abstract This study provides novel mechanistic insights into how acute mental stress fuels vascular inflammation and promotes plaque rupture. EC, endothelial cells; HPA, hypothalamic-pituitary-adrenal axis; MACS, macrophages; SAM, sympathetic-adrenal-medullary axis.
- Published
- 2020
25. Neutrophils Recirculate through Lymph Nodes to Survey Tissues for Pathogens
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Eugene C. Butcher, Ania Bogoslowski, Christoph Scheiermann, Craig N. Jenne, Paul Kubes, Woo Young Lee, Douglas A. Steeber, Samer Alanani, David Masopust, Chien Sin Chen, and Sathi Wijeyesinghe
- Subjects
Male ,Neutrophils ,Immunology ,High endothelial venules ,Efferent lymphatics ,Population ,ddc:616.07 ,Biology ,Mice ,Immune system ,Venules ,medicine ,Immunology and Allergy ,Animals ,Endothelium ,Lymphocytes ,L-Selectin ,education ,Lymph node ,Sphingosine-1-Phosphate Receptors ,Lymphatic Vessels ,education.field_of_study ,Microbiota ,Staphylococcal Infections ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Lymphatic system ,Neutrophil Infiltration ,Female ,Lymph ,Lymph Nodes ,Neutrophil recruitment - Abstract
The adaptive immune function of lymph nodes is dependent on constant recirculation of lymphocytes. In this article, we identify neutrophils present in the lymph node at steady state, exhibiting the same capacity for recirculation. In germ-free mice, neutrophils still recirculate through lymph nodes, and in mice cohoused with wild microbiome mice, the level of neutrophils in lymph nodes increases significantly. We found that at steady state, neutrophils enter the lymph node entirely via L-selectin and actively exit via efferent lymphatics via an S1P dependent mechanism. The small population of neutrophils in the lymph node can act as reconnaissance cells to recruit additional neutrophils in the event of bacterial dissemination to the lymph node. Without these reconnaissance cells, there is a delay in neutrophil recruitment to the lymph node and a reduction in swarm formation following Staphylococcus aureus infection. This ability to recruit additional neutrophils by lymph node neutrophils is initiated by LTB4. This study establishes the capacity of neutrophils to recirculate, much like lymphocytes via L-selectin and high endothelial venules in lymph nodes and demonstrates how the presence of neutrophils at steady state fortifies the lymph node in case of an infection disseminating through lymphatics.
- Published
- 2020
26. Molecular Interactions Between Components of the Circadian Clock and the Immune System
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Stephan Holtkamp, Sophia Martina Hergenhan, and Christoph Scheiermann
- Subjects
Protein family ,animal diseases ,Circadian clock ,CLOCK Proteins ,chemical and pharmacologic phenomena ,Inflammation ,ddc:616.07 ,Biology ,Methylation ,rhythm ,Article ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Structural Biology ,Circadian Clocks ,Histone methylation ,medicine ,Animals ,Humans ,Circadian rhythm ,Molecular Biology ,Psychological repression ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Acetylation ,biochemical phenomena, metabolism, and nutrition ,Circadian Rhythm ,3. Good health ,Cell biology ,immune system ,circadian ,Gene Expression Regulation ,inflammation ,bacteria ,medicine.symptom ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
The immune system is under control of the circadian clock. Many of the circadian rhythms observed in the immune system originate in direct interactions between components of the circadian clock and components of the immune system. The main means of circadian control over the immune system is by direct control of circadian clock proteins acting as transcription factors driving the expression or repression of immune genes. A second circadian control of immunity lies in the acetylation or methylation of histones to regulate gene transcription or inflammatory proteins. Furthermore, circadian clock proteins can engage in direct physical interactions with components of key inflammatory pathways such as members of the NFκB protein family. This regulation is transcription independent and allows the immune system to also reciprocally exert control over circadian clock function. Thus, the molecular interactions between the circadian clock and the immune system are manifold. We highlight and discuss here the recent findings with respect to the molecular mechanisms that control time-of-day-dependent immunity. This review provides a structured overview focusing on the key circadian clock proteins and discusses their reciprocal interactions with the immune system., Graphical abstract Image 1, Highlights • The immune system is under control of the circadian clock. • Circadian clock proteins act as transcription factors controlling genes of the immune system. • Circadian clock proteins engage in direct physical interactions with inflammatory proteins. • Immune factors also reciprocally exert control over circadian clock function.
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- 2020
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27. Clocking in to immunity
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Andrew S. I. Loudon, Louise Ince, Christoph Scheiermann, and Julie E. Gibbs
- Subjects
0301 basic medicine ,History ,medicine.medical_treatment ,Circadian clock ,Clockwork ,Adaptive Immunity ,Biology ,Education ,03 medical and health sciences ,Immune system ,Immunity ,Circadian Clocks ,medicine ,Animals ,Humans ,Lymphocytes ,Circadian rhythm ,Chronotherapy ,Innate immune system ,Chronotherapy (sleep phase) ,Models, Immunological ,Acquired immune system ,Immunity, Innate ,Circadian Rhythm ,Gastrointestinal Microbiome ,Computer Science Applications ,030104 developmental biology ,Host-Pathogen Interactions ,Immunotherapy ,Seasons ,Neuroscience - Abstract
Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.
- Published
- 2018
28. In memory of a game-changing haematologist
- Author
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Andrés Hidalgo, Daniel Lucas, and Christoph Scheiermann
- Subjects
Cognitive science ,Cell biology ,History ,Multidisciplinary ,Careers ,Computer science ,ddc:616.07 - Published
- 2021
29. Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses
- Author
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Rainer Haas, Hanspeter Herzel, Werner Solbach, Leif E. Sander, Louise Ince, Marc Ehlers, Kerstin Kraus, Olaf Uhl, Ute Harrison, Anthony H. Tsang, David Druzd, Wenyan He, Alexei Leliavski, Berthold Koletzko, Christoph Scheiermann, Naoto Kawakami, Alba de Juan, Olga Matveeva, Henrik Oster, Christoph Schmal, Chien-Sin Chen, Ling Yao, and Sophia Martina Hergenhan
- Subjects
0301 basic medicine ,Lymphocyte ,Circadian clock ,Immunology ,Experimental/immunology ,Fluorescent Antibody Technique ,Adaptive Immunity/immunology ,Lymphocytes/immunology ,Circadian Clocks/immunology ,Lymph Nodes/immunology ,Biology ,Inbred C57BL ,Real-Time Polymerase Chain Reaction ,Transgenic ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Lymph node stromal cell ,medicine ,Animals ,Leukocyte/immunology ,Immunology and Allergy ,Encephalomyelitis ,Lymphocyte homing receptor ,Lymph node ,Chemotaxis ,Immunologic Surveillance/immunology ,Dendritic cell ,Flow Cytometry ,Adoptive Transfer ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Lymphatic system ,Infectious Diseases ,Lymph ,030217 neurology & neurosurgery ,Autoimmune - Abstract
Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.
- Published
- 2017
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30. Author Correction: Yolk sac macrophage progenitors traffic to the embryo during defined stages of development
- Author
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Simon Yona, Robert Pick, Markus Sperandio, Tobias Weinberger, Raffael Thaler, Andreas Margraf, Elvira Mass, Jeffery D. Molkentin, Christoph Scheiermann, F. Wagner, Hellen Ishikawa-Ankerhold, Udo Jeschke, Christopher Stremmel, Jon Frampton, Sarah Klapproth, Markus Moser, Ronald J. Vagnozzi, Stefan Hutter, Frederic Geissmann, Christian Schulz, Steffen Massberg, and R. Schuchert
- Subjects
0301 basic medicine ,Multidisciplinary ,Science ,General Physics and Astronomy ,Embryo ,General Chemistry ,Anatomy ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Macrophage (ecology) ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,medicine ,lcsh:Q ,Yolk sac ,lcsh:Science - Abstract
This article contains errors in Figs. 5 and 6, for which we apologize. In Fig. 5f, the image ‘E12.5 tail’ was inadvertently replaced with a duplicate of the image ‘E12.5 trunk’ from the same panel. In Figure 6d, the image ‘E9.5/OH-TAM E8.5, embryo’ was inadvertently replaced with a duplicate of the image ‘E10.5/ OH-TAM E8.5, embryo’ from Fig. 6b. The corrected versions of these figures appear in the Author Correction associated with this Article.
- Published
- 2018
31. Time-of-Day-Dependent Trafficking and Function of Leukocyte Subsets
- Author
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Wenyan He, Chien-Sin Chen, Robert Pick, and Christoph Scheiermann
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Leukocyte migration ,Chemokine ,Time Factors ,Immunology ,Inflammation ,Adaptive Immunity ,ddc:616.07 ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Leukocytes ,medicine ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,030304 developmental biology ,0303 health sciences ,biology ,Cell adhesion molecule ,Chemotaxis ,Acquired immune system ,Immunity, Innate ,Circadian Rhythm ,3. Good health ,CLOCK ,Chemotaxis, Leukocyte ,Organ Specificity ,biology.protein ,Disease Susceptibility ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
The number of leukocytes circulating in blood in mammals is under circadian control (i.e., ∼24h). We summarize here latest findings on the mechanisms governing leukocyte migration from the blood into various organs, focusing on the distinct leukocyte subtype- and tissue-specific molecules involved. We highlight the oscillatory expression patterns of adhesion molecules, chemokines, and their receptors that are expressed on endothelial cells and leukocytes, and which are crucial regulators of rhythmic leukocyte recruitment. We also discuss the relevance of clock genes for leukocyte function and migration. Finally, we compare immune cell rhythms under steady-state conditions as well as during inflammation and disease, and we postulate how these findings provide potential new avenues for therapeutic intervention.
- Published
- 2019
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32. Differential requirement of kindlin-3 for T cell progenitor homing to the non-vascularized and vascularized thymus
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Christoph Scheiermann, Robert Pick, Raphael Ruppert, Markus Sperandio, Jasmin Weber, Reinhard Fässler, Markus Moser, Andreas Margraf, Sarah Klapproth, and Federico A. Moretti
- Subjects
0301 basic medicine ,Mouse ,integrin ,QH301-705.5 ,T-Lymphocytes ,T cell ,Science ,Neovascularization, Physiologic ,Thymus Gland ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immunology and Inflammation ,0302 clinical medicine ,Cell Adhesion ,medicine ,Animals ,Cytotoxic T cell ,Progenitor cell ,Biology (General) ,Antigen-presenting cell ,Cell Proliferation ,Progenitor ,Thymocytes ,General Immunology and Microbiology ,kindlin-3 ,Stem Cells ,General Neuroscience ,General Medicine ,T cell homing ,Cell biology ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,Liver ,030220 oncology & carcinogenesis ,thymus development ,T cell migration ,Medicine ,Atrophy ,Blood Flow Velocity ,Research Article ,Developmental Biology ,Homing (hematopoietic) - Abstract
The role of integrin-mediated adhesion during T cell progenitor homing to and differentiation within the thymus is ill-defined, mainly due to functional overlap. To circumvent compensation, we disrupted the hematopoietic integrin regulator kindlin-3 in mice and found a progressive thymus atrophy that is primarily caused by an impaired homing capacity of T cell progenitors to the vascularized thymus. Notably, the low shear flow conditions in the vascular system at midgestation allow kindlin-3-deficient fetal liver-derived T cell progenitors to extravasate via pharyngeal vessels and colonize the avascular thymus primordium. Once in the thymus, kindlin-3 promotes intrathymic T cell proliferation by facilitating the integrin-dependent crosstalk with thymic antigen presenting cells, while intrathymic T cell migration, maturation into single positive CD4 and CD8 T cells and release into the circulation proceed without kindlin-3. Thus, kindlin-3 is dispensable for integrin-mediated T cell progenitor adhesion and signalling at low and indispensable at high shear forces.
- Published
- 2018
33. Author response: Differential requirement of kindlin-3 for T cell progenitor homing to the non-vascularized and vascularized thymus
- Author
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Markus Moser, Robert Pick, Markus Sperandio, Christoph Scheiermann, Reinhard Fässler, Federico A. Moretti, Jasmin Weber, Andreas Margraf, Raphael Ruppert, and Sarah Klapproth
- Subjects
medicine.anatomical_structure ,T cell ,medicine ,Biology ,Homing (hematopoietic) ,Progenitor ,Cell biology - Published
- 2018
34. Loss of local innervation induces lymph node expansion
- Author
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Chien-Sin Chen, Louise Ince, and Christoph Scheiermann
- Subjects
Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,Genetics ,medicine ,Biology ,Molecular Biology ,Biochemistry ,Lymph node ,Biotechnology - Published
- 2018
35. Chrono-pharmacological Targeting of the CCL2-CCR2 Axis Ameliorates Atherosclerosis
- Author
-
Ariane Schumski, Renske J. de Jong, Christoph Scheiermann, Almudena Ortega-Gomez, Oliver Soehnlein, Carla Winter, Christian Weber, Michael Hristov, Hessel Poelman, Gerry A. F. Nicolaes, Carlos Silvestre-Roig, Roland Immler, Markus Sperandio, Maik Drechsler, Andrés Hidalgo, Joana R. Viola, Patricia Lemnitzer, Janine Winter, Tanja Zeller, Promovendi CD, RS: CARIM - R1.01 - Blood proteins & engineering, Biochemie, and RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis
- Subjects
0301 basic medicine ,RECRUITMENT ,EXPRESSION ,medicine.medical_specialty ,CCR2 ,Myeloid ,Physiology ,Receptors, CCR2 ,LEUKOCYTE ,Inflammation ,030204 cardiovascular system & hematology ,CCL2 ,CIRCADIAN CLOCK ,ADHESION ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Cell Adhesion ,Animals ,Myeloid Cells ,Circadian rhythm ,Cell adhesion ,HYPERLIPIDEMIA ,Molecular Biology ,Chemokine CCL2 ,Mice, Knockout ,business.industry ,Mesenchymal Stem Cells ,Cell Biology ,Atherosclerosis ,Phenotype ,3. Good health ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,MYOCARDIAL-INFARCTION ,MONOCYTES ,medicine.symptom ,business ,LY6C(HI) ,Signal Transduction - Abstract
Onset of cardiovascular complications as a consequence of atherosclerosis exhibits a circadian incidence with a peak in the morning hours. Although development of atherosclerosis extends for long periods of time through arterial leukocyte recruitment, we hypothesized that discrete diurnal invasion of the arterial wall could sustain atherogenic growth. Here, we show that myeloid cell recruitment to atherosclerotic lesions oscillates with a peak during the transition from the activity to the resting phase. This diurnal phenotype is regulated by rhythmic release of myeloid cell-derived CCL2, and blockade of its signaling abolished oscillatory leukocyte adhesion. In contrast, we show that myeloid cell adhesion to microvascular beds peaks during the early activity phase. Consequently, timed pharmacological CCR2 neutralization during the activity phase caused inhibition of atherosclerosis without disturbing microvascular recruitment. These findings demonstrate that chronic inflammation of large vessels feeds on rhythmic myeloid cell recruitment, and lay the foundation for chrono-pharmacology-based therapy.
- Published
- 2018
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36. Loss of local innervation induces lymph node expansion
- Author
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Chien-Sin Chen, Louise Ince, Alba de Juan, and Christoph Scheiermann
- Subjects
Immunology ,Immunology and Allergy - Abstract
The nervous system directly innervates both lymphoid and non-lymphoid tissues, but the influence of neural input on regional immune responses remains unclear. Local, unilateral deprivation of nerves to the popliteal lymph node (popLN) and its draining area by surgical denervation led to ipsilateral paw thickening and dramatic nodal expansion of all leukocyte subsets investigated. However, denervation surgeries on nerves bypassing the popLN, such as cutting the femoral nerve, the sciatic nerve below the popliteal fossa or individual branches of the sciatic nerve, failed to increase lymph node cellularity. Expansion was associated with increased expression of Cxcl13, Il1a, Il1b, Il6, Il10, Il17a and Il17f levels in denervated popLNs and paws. Adoptive cell transfer revealed enhanced cellular trafficking of lymphocytes to the lymph node, accounting for increased cellularity as this was ablated in mice receiving antibodies blocking lymph node homing. Additionally, immunofluorescence analyses revealed high levels of B cell proliferation and germinal center formation, which was mirrored by enhanced antibody titers in serum. Blockade of antigen presentation using an MHC class II-neutralizing antibody or surgically ablating drainage of afferent lymphatics to the popLN inhibited denervation-induced nodal expansion. Together, these data provide evidence for an important regulatory role of direct neural innervation in local immune responses.
- Published
- 2019
37. Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues
- Author
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Chien-Sin Chen, Sophia Martina Hergenhan, Alba de Juan, Paul F. Bradfield, Christoph Scheiermann, Michel Aurrand-Lions, David Druzd, Stephan Holtkamp, Robert Pick, Wenyan He, Markus Sperandio, Louise Ince, Jeoffrey Pelletier, Susanne Bierschenk, Jasmin Weber, Julien Martin Pierre Grenier, Kerstin Kraus, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Deutsches Zentrum für Herz-Kreislaufforschung, Inca-Inserm-DGOS 6038, European Research Council, SCHE 1645/2-1, German Research, German Ministry of Education and Research, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,0301 basic medicine ,Leukocyte migration ,[SDV]Life Sciences [q-bio] ,Circadian clock ,ddc:616.07 ,Inbred C57BL ,migration ,Transgenic ,Mice ,Cell Movement ,Circadian Rhythm/immunology ,Leukocyte Trafficking ,Leukocytes ,Homeostasis ,Immunology and Allergy ,10. No inequality ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,Regulation of gene expression ,Cell Movement/genetics/immunology ,Middle Aged ,16. Peace & justice ,Circadian Rhythm ,Cell biology ,Infectious Diseases ,Organ Specificity ,Female ,Organ Specificity/genetics/immunology ,medicine.symptom ,Endothelial Cells/immunology/metabolism ,Homeostasis/genetics/immunology ,leukocyte ,Adult ,Knockout ,Immunology ,Mice, Transgenic ,Inflammation ,Biology ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,Circadian rhythm ,Gene Expression Regulation/immunology ,Gene Expression Profiling ,Endothelial Cells ,Cell Adhesion Molecules/genetics/immunology/metabolism ,Mice, Inbred C57BL ,Gene expression profiling ,Transcription Factors/genetics/immunology/metabolism ,circadian ,030104 developmental biology ,Gene Expression Regulation ,Leukocytes/cytology/immunology/metabolism ,Cell Adhesion Molecules ,Transcription Factors ,Homing (hematopoietic) - Abstract
Summary The number of leukocytes present in circulation varies throughout the day, reflecting bone marrow output and emigration from blood into tissues. Using an organism-wide circadian screening approach, we detected oscillations in pro-migratory factors that were distinct for specific vascular beds and individual leukocyte subsets. This rhythmic molecular signature governed time-of-day-dependent homing behavior of leukocyte subsets to specific organs. Ablation of BMAL1, a transcription factor central to circadian clock function, in endothelial cells or leukocyte subsets demonstrated that rhythmic recruitment is dependent on both microenvironmental and cell-autonomous oscillations. These oscillatory patterns defined leukocyte trafficking in both homeostasis and inflammation and determined detectable tumor burden in blood cancer models. Rhythms in the expression of pro-migratory factors and migration capacities were preserved in human primary leukocytes. The definition of spatial and temporal expression profiles of pro-migratory factors guiding leukocyte migration patterns to organs provides a resource for the further study of the impact of circadian rhythms in immunity., Graphical Abstract, Highlights • Leukocyte subsets show time-of-day-dependent migration patterns to organs • This relies on lineage- and tissue-specific oscillations in pro-migratory factors • Loss of circadian clocks in the endothelium or leukocytes ablates rhythmicity • The efficacy of blocking leukocyte migration is time-of-day dependent, Leukocytes continuously circulate throughout the body. He et al. demonstrate that trafficking patterns of major leukocyte subsets occur in a rhythmic manner dependent on the time-of-day-dependent expression of lineage- and tissue-specific factors. This influences the inflammatory response and leukemic tumor burden and translates to the migration behavior of human primary lymphocytes.
- Published
- 2018
38. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration
- Author
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Colleen Barrick, Yuya Kunisaki, Christoph Scheiermann, Lino Tessarollo, Daniel Lucas, Paul S. Frenette, Andrew Chow, and Ingmar Bruns
- Subjects
Pathology ,medicine.medical_specialty ,Sympathetic Nervous System ,Regeneration/drug effects ,Cell Survival ,Antineoplastic Agents ,General Biochemistry, Genetics and Molecular Biology ,Receptors, Adrenergic, beta/physiology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents/toxicity ,Bone Marrow ,Receptors, Adrenergic, beta ,Genetic model ,medicine ,Glial cell line-derived neurotrophic factor ,Animals ,Regeneration ,Sympathetic Nervous System/drug effects/physiology ,Hematopoietic Stem Cell Mobilization ,030304 developmental biology ,0303 health sciences ,biology ,Regeneration (biology) ,Hematopoietic Tissue ,Hematopoietic Stem Cells/drug effects ,General Medicine ,Nerve injury ,Hematopoietic Stem Cells ,Neuroregeneration ,Bone Marrow/drug effects/innervation ,3. Good health ,Mice, Inbred C57BL ,Neuroprotective Agents ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Bone marrow ,medicine.symptom ,Neuroprotective Agents/pharmacology - Abstract
Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury.
- Published
- 2013
39. Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche and a Stepping-Stone for Regenerative Medicine
- Author
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Daniel Lucas, Sandra Pinho, Christoph Scheiermann, and Paul S. Frenette
- Subjects
Hematopoietic Stem Cell Transplantation/methods ,Regenerative Medicine/methods ,Hematopoietic stem cell niche ,Immunology ,Clinical uses of mesenchymal stem cells ,Bone Marrow Cells ,Biology ,Bone Marrow Cells/immunology/pathology ,Mesenchymal Stem Cell Transplantation ,Regenerative Medicine ,Inflammation/immunology/pathology/therapy ,medicine ,Animals ,Humans ,Immunology and Allergy ,Progenitor cell ,Stem cell transplantation for articular cartilage repair ,Inflammation ,Stem Cells ,Mesenchymal stem cell ,Hematopoietic Stem Cell Transplantation ,Stem Cells/immunology ,Cell biology ,medicine.anatomical_structure ,Mesenchymal Stem Cell Transplantation/methods ,Stromal Cells/immunology/pathology/transplantation ,Bone marrow ,Stromal Cells ,Stem cell ,Adult stem cell - Abstract
Mesenchymal stem cells (MSCs) are self-renewing precursor cells that can differentiate into bone, fat, cartilage, and stromal cells of the bone marrow. Recent studies suggest that MSCs themselves are critical for forming a niche that maintains hematopoietic stem cells (HSCs). The ease by which human MSC-like and stromal progenitor cells can be isolated from the bone marrow and other tissues has led to the rapid development of clinical investigations exploring their anti-inflammatory properties, tissue preservation capabilities, and regenerative potential. However, the identity of genuine MSCs and their specific contributions to these various beneficial effects have remained enigmatic. In this article, we examine the definition of MSCs and discuss the importance of rigorously characterizing their stem cell activity. We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications.
- Published
- 2013
40. Circadian control of the immune system
- Author
-
Yuya Kunisaki, Christoph Scheiermann, and Paul S. Frenette
- Subjects
History ,Transcription, Genetic ,Physiological/physiology ,Mammals/immunology/physiology ,Adaptive Immunity ,Circadian Rhythm Signaling Peptides and Proteins/genetics/physiology ,Chronobiology Disorders/immunology ,Mice ,Models ,Circadian Rhythm/immunology ,Hormones/physiology ,Feedback, Physiological ,Mammals ,Circadian Rhythm Signaling Peptides and Proteins ,Drug Chronotherapy ,Acquired immune system ,Bacterial circadian rhythms ,Circadian Rhythm ,Computer Science Applications ,Immunological ,Disease Susceptibility ,medicine.symptom ,Transcription ,Inflammation/immunology/physiopathology ,Inflammation ,Biology ,Chronobiology Disorders ,Article ,Feedback ,Education ,Immune system ,Immunity ,medicine ,Animals ,Humans ,Circadian rhythm ,Adaptive Immunity/physiology ,Gene Expression Regulation/physiology ,Models, Immunological ,Genetic/physiology ,biochemical phenomena, metabolism, and nutrition ,Immune System/physiology ,Hormones ,Blood Cell Count ,Immunity, Humoral ,Gene Expression Regulation ,Light effects on circadian rhythm ,Immune System ,Immunology ,Humoral/physiology ,bacteria ,Neuroscience - Abstract
Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.
- Published
- 2013
41. Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice
- Author
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Camila B. Almeida, Jung Eun Jang, Nicola Conran, Christoph Scheiermann, Colette Prophete, Fernando Ferreira Costa, and Paul S. Frenette
- Subjects
Male ,Erythrocytes ,Pyrazoles/pharmacology ,Leukocytes/cytology/drug effects ,3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors/metabolism ,Cell Communication ,Pharmacology ,Biochemistry ,Mice ,chemistry.chemical_compound ,Vascular Diseases/chemically induced/drug therapy/metabolism ,Antisickling Agents ,Leukocytes ,Antisickling Agents/therapeutic use ,Hydroxyurea ,Cell Adhesion/drug effects ,Pyrimidines/pharmacology ,Cyclic GMP ,Cell adhesion molecule ,Phosphodiesterase ,Hematology ,medicine.anatomical_structure ,Endothelium, Vascular/cytology/drug effects/metabolism ,Acute Disease ,Female ,Tumor necrosis factor alpha ,Hydroxyurea/therapeutic use ,Endothelium ,Immunology ,Leukocyte Rolling ,Anemia, Sickle Cell ,Biology ,Erythrocytes/cytology/drug effects ,Nitric oxide ,Red Cells, Iron, and Erythropoiesis ,Anemia, Sickle Cell/chemically induced/drug therapy/metabolism ,Cell Adhesion ,medicine ,Animals ,Humans ,Vascular Diseases ,Cell adhesion ,Cyclic guanosine monophosphate ,Tumor Necrosis Factor-alpha ,Tumor Necrosis Factor-alpha/toxicity ,Cell Biology ,Mice, Inbred C57BL ,Cyclic GMP/metabolism ,Disease Models, Animal ,Pyrimidines ,chemistry ,3',5'-Cyclic-AMP Phosphodiesterases ,Pyrazoles ,Endothelium, Vascular - Abstract
Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD–mouse-model of tumor necrosis factor-α–induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)–signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.
- Published
- 2012
42. Regulation of Immunity by the Circadian Clock
- Author
-
Louise Ince, Alba de Juan, Christoph Scheiermann, and David Druzd
- Subjects
0301 basic medicine ,Chemokine ,medicine.medical_treatment ,Circadian clock ,Molecular evidence ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cytokine ,Immune system ,Immunity ,Immunology ,biology.protein ,medicine ,Circadian rhythm ,030217 neurology & neurosurgery - Abstract
Over the last few years, molecular evidence has clearly shown a direct impact of daily rhythms on the immune system, both in steady state and under inflammatory conditions. Circadian oscillations have been demonstrated in the regulation of cytokine and chemokine levels as well as immune cell numbers in blood and tissues. A possible explanation for these rhythms is that species are more prone to be exposed to a variety of acute threats such as injuries and microbial infections at specific times during their circadian cycle. Also some chronic diseases follow a circadian rhythm, indicating that a greater understanding of the underlying molecular mechanisms will permit the development of new and improved therapeutic strategies for treating inflammatory diseases that incorporate the element of time.
- Published
- 2016
43. The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment
- Author
-
Maximilian J. Schloss, Michael Horckmans, Maik Drechsler, Johan Duchene, Sabine Steffens, Katrin Nitz, Kiril Bidzhekov, Christian Weber, Oliver Soehnlein, Christoph Scheiermann, Biochemie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, Pathologie, RS: CARIM - R1.01 - Blood proteins & engineering, and Pathology
- Subjects
0301 basic medicine ,Chemokines -- metabolism ,Chemokine ,Myeloid ,Myocardial Infarction ,ddc:616.07 ,Inbred C57BL ,Cardiovascular System ,Mice ,neutrophils ,Fibrosis ,CXC chemokine receptors ,Myocardial infarction ,Research Articles ,Cause of death ,biology ,Sciences bio-médicales et agricoles ,Chemokines/metabolism ,3. Good health ,medicine.anatomical_structure ,Neutrophil Infiltration ,Cardiology ,cardiovascular system ,Molecular Medicine ,Female ,Chemokines ,Research Article ,Cardiac function curve ,circadian rhythm ,medicine.medical_specialty ,Immunology ,Myocardial Infarction -- pathology -- physiopathology ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Progenitor cell ,progenitors ,Myocardial Infarction/pathology/physiopathology ,Animal ,business.industry ,fibrosis ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,myocardial infarction healing ,Cardiovascular and Metabolic Diseases ,Disease Models ,biology.protein ,business - Abstract
Myocardial infarction (MI) is the leading cause of death in Western countries. Epidemiological studies show acute MI to be more prevalent in the morning and to be associated with a poorer outcome in terms of mortality and recovery. The mechanisms behind this association are not fully understood. Here, we report that circadian oscillations of neutrophil recruitment to the heart determine infarct size, healing, and cardiac function after MI Preferential cardiac neutrophil recruitment during the active phase (Zeitgeber time, ZT13) was paralleled by enhanced myeloid progenitor production, increased circulating numbers of CXCR2(hi) neutrophils as well as upregulated cardiac adhesion molecule and chemokine expression. MI at ZT13 resulted in significantly higher cardiac neutrophil infiltration compared to ZT5, which was inhibited by CXCR2 antagonism or neutrophil-specific CXCR2 knockout. Limiting exaggerated neutrophilic inflammation at this time point significantly reduced the infarct size and improved cardiac function., info:eu-repo/semantics/published
- Published
- 2016
44. Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment
- Author
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Renske J. de Jong, Barbara Walzog, Christian Weber, Robert Pick, Almudena Ortega-Gomez, Patricia Lemnitzer, Jochen Grommes, Wolfgang Siess, Remco T. A. Megens, Janina Jamasbi, Christoph Scheiermann, Alexander Zarbock, Jan Rossaint, Janine Brauner, Maik Drechsler, Jessica Tilgner, Oliver Soehnlein, Yvonne Döring, Christine T. N. Pham, Melanie Salvermoser, Pathology, Biomedische Technologie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, Biochemie, and Pathologie
- Subjects
0301 basic medicine ,Pathology ,Myeloid ,Myeloid Cells/immunology/metabolism ,cathepsin G ,Integrins/metabolism ,030204 cardiovascular system & hematology ,Cathepsin G ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Venules ,Cathepsin G/antagonists & inhibitors/genetics/metabolism ,Medicine ,Myeloid Cells ,Chemokine CCL5 ,Mice, Knockout ,Chemotaxis ,Arteries ,focal adhesions ,medicine.anatomical_structure ,Atherosclerosis/drug therapy/etiology/metabolism/pathology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Shear Strength ,Intravital microscopy ,Chemokine CCL5/genetics/metabolism ,Protein Binding ,medicine.medical_specialty ,Cell Adhesion/genetics ,Knockout ,Context (language use) ,Inflammation ,Article ,Microcirculation ,Vascular/metabolism/pathology ,Focal adhesion ,03 medical and health sciences ,Physiology (medical) ,Cell Adhesion ,Animals ,Humans ,Leukocyte Rolling ,Endothelium ,Cell adhesion ,business.industry ,Animal ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immunology ,Disease Models ,integrins ,Endothelium, Vascular ,Chemotaxis/genetics/immunology ,atherosclerosis ,business ,Biomarkers - Abstract
Background: Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the context of arterial myeloid cell recruitment. Methods: Intravital microscopy of the carotid artery, the jugular vein, and cremasteric arterioles and venules in Apoe –/– and CatG-deficient mice ( Apoe –/– Ctsg –/– ) was used to study site-specific myeloid cell behavior after high-fat diet feeding or tumor necrosis factor stimulation. Atherosclerosis development was assessed in aortic root sections after 4 weeks of high-fat diet, whereas lung inflammation was assessed after inhalation of lipopolysaccharide. Endothelial deposition of CatG and CCL5 was quantified in whole-mount preparations using 2-photon and confocal microscopy. Results: Our observations elucidated a crucial role for CatG during arterial leukocyte adhesion, an effect not found during venular adhesion. Consequently, CatG deficiency attenuates atherosclerosis but not acute lung inflammation. Mechanistically, CatG is immobilized on arterial endothelium where it activates leukocytes to firmly adhere engaging integrin clustering, a process of crucial importance to achieve effective adherence under high-shear flow. Therapeutic neutralization of CatG specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of CatG-neutralizing antibodies permitted inhibition of atherogenesis in mice. Conclusions: Taken together, these findings present evidence of an arterial-specific recruitment pattern centered on CatG-instructed adhesion strengthening. The inhibition of this process could provide a novel strategy for treatment of arterial inflammation with limited side effects.
- Published
- 2016
45. Rac signal adaptation controls neutrophil mobilization from the bone marrow
- Author
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Giulia Germena, Christoph Scheiermann, Irene Franco, Andrea Antonio Gamba, Augusta Di Savino, Alessandra Ghigo, Remco T. A. Megens, Emilio Hirsch, Francesca Copperi, Markus Sperandio, Angela R.M. Kurz, Miriam Martini, Anna Sapienza, Alessia Perino, Elisa Ciraolo, Carlo Cosimo Campa, Annalisa Camporeale, Biomedische Technologie, RS: CARIM School for Cardiovascular Diseases, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, and RS: CARIM - R1.01 - Blood proteins & engineering
- Subjects
0301 basic medicine ,Chemokine ,Receptors, CXCR4 ,Neutrophils ,Knockout ,CXCR4 ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Bone Marrow ,Receptors ,medicine ,Animals ,CXC chemokine receptors ,Receptor ,Molecular Biology ,Mice, Knockout ,biology ,Signal Transduction/physiology ,GTPase-Activating Proteins ,Cell migration ,Chemotaxis ,Cell Biology ,CXCR4/genetics/metabolism ,Chemokine CXCL12 ,Cell biology ,rac GTP-Binding Proteins ,CXCL2 ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,GTPase-Activating Proteins/genetics/metabolism ,Immunology ,Bone Marrow/enzymology ,biology.protein ,Neutrophils/enzymology ,Bone marrow ,Rac GTP-Binding Proteins/genetics/metabolism ,Chemokine CXCL12/genetics/metabolism ,Signal Transduction - Abstract
Mobilization of neutrophils from the bone marrow determines neutrophil blood counts and thus is medically important. Balanced neutrophil mobilization from the bone marrow depends on the retention-promoting chemokine CXCL12 and its receptor CXCR4 and the egression-promoting chemokine CXCL2 and its receptor CXCR2. Both pathways activate the small guanosine triphosphatase Rac, leaving the role of this signaling event in neutrophil retention and egression ambiguous. On the assumption that active Rac determines persistent directional cell migration, we generated a mathematical model to link chemokine-mediated Rac modulation to neutrophil egression time. Our computer simulation indicated that, in the bone marrow, where the retention signal predominated, egression time strictly depended on the time it took Rac to return to its basal activity (namely, adaptation). This prediction was validated in mice lacking the Rac inhibitor ArhGAP15. Neutrophils in these mice showed prolonged Rac adaptation and cell-autonomous retention in the bone marrow. Our model thus demonstrates that mobilization in the presence of two spatially defined opposing chemotactic cues strictly depends on inhibitors shaping the time course of signal adaptation. Furthermore, our findings might help to find new modes of intervention to treat conditions characterized by excessively low or high circulating neutrophils.
- Published
- 2016
46. Bone marrow CD169(+) macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche
- Author
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Nico van Rooijen, Daigo Hashimoto, Andrew Chow, Marylene Leboeuf, Masato Tanaka, Christoph Scheiermann, Daniel Lucas, Miriam Merad, Colette Prophete, Andrés Hidalgo, Paul S. Frenette, Simón Méndez-Ferrer, Michela Battista, Molecular cell biology and Immunology, and CCA - Immuno-pathogenesis
- Subjects
Male ,Sialic Acid Binding Ig-like Lectin 1 ,Fluorescent Antibody Technique ,Polymerase Chain Reaction ,Monocytes ,Mice ,0302 clinical medicine ,Monocytes/metabolism ,Immunology and Allergy ,Homeostasis ,Receptors, Immunologic ,Bone Marrow Cells/cytology/metabolism ,Mice, Knockout ,0303 health sciences ,Membrane Glycoproteins ,Receptor Cross-Talk/immunology ,Membrane Glycoproteins/metabolism ,Flow Cytometry ,Hematopoietic Stem Cell Mobilization ,Cell biology ,Interleukin-10 ,Haematopoiesis ,medicine.anatomical_structure ,Homeostasis/immunology ,Stem cell ,Hematopoietic stem cell niche ,Immunology ,Receptors, Immunologic/metabolism ,Bone Marrow Cells ,Enzyme-Linked Immunosorbent Assay ,Biology ,Article ,Colony-Forming Units Assay ,03 medical and health sciences ,Macrophages/metabolism ,medicine ,Chemokine CXCL12/metabolism ,Animals ,Progenitor cell ,Mesenchymal Stromal Cells/cytology ,030304 developmental biology ,DNA Primers ,Interleukin-10/genetics ,DNA Primers/genetics ,Hematopoietic Stem Cells/cytology ,Macrophages ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Receptor Cross-Talk ,Nestin ,Hematopoietic Stem Cells ,Molecular biology ,Chemokine CXCL12 ,Mice, Inbred C57BL ,Bone marrow ,030215 immunology - Abstract
Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1hi monocytes (MOs), Gr-1lo MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin+ niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169+ MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin+ niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
- Published
- 2011
47. Junctional Adhesion Molecule-C Mediates Leukocyte Infiltration in Response to Ischemia Reperfusion Injury
- Author
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Costantino Pitzalis, Sussan Nourshargh, Alessandra Marrelli, Michel Aurrand-Lions, Christoph Scheiermann, Christoph Thiemermann, Paolo Meda, Nimesh S. A. Patel, Beat A. Imhof, Abigail Woodfin, Bartomeu Colom, and Mathieu-Benoit Voisin
- Subjects
Leukocyte migration ,Pathology ,medicine.medical_specialty ,Immunoelectron microscopy ,education ,Immunoglobulins ,Mice, Transgenic ,ddc:616.07 ,Endothelial Cells/metabolism ,Kidney ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Adhesion ,Leukocytes ,medicine ,Animals ,ddc:612 ,Muscle, Skeletal ,Cell adhesion ,030304 developmental biology ,Leukocytes/physiology ,0303 health sciences ,Kidney/blood supply ,Cell adhesion molecule ,business.industry ,Cell Adhesion Molecules/analysis/physiology ,fungi ,Endothelial Cells ,medicine.disease ,humanities ,Cell biology ,Mice, Inbred C57BL ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Cremaster muscle ,cardiovascular system ,Muscle, Skeletal/blood supply ,Reperfusion Injury/pathology ,Cardiology and Cardiovascular Medicine ,business ,Cell Adhesion Molecules ,Junctional Adhesion Molecule C ,Reperfusion injury ,Immunoglobulins/analysis/physiology ,Intravital microscopy - Abstract
Objective—Junctional adhesion molecule-C (JAM-C) is an adhesion molecule that has multiple roles in inflammation and vascular biology, but many aspects of its functions under pathological conditions are unknown. Here we investigated the role of JAM-C in leukocyte migration in response to ischemia reperfusion (I/R) injury.Methods and Results—Pretreatment of mice with soluble JAM-C (sJAM-C), used as a pharmacological blocker of JAM-C-mediated reactions, significantly suppressed leukocyte migration in models of kidney and cremaster muscle I/R injury (39 and 51% inhibition, respectively). Furthermore, in the cremaster muscle model (studied by intravital microscopy), both leukocyte adhesion and transmigration were suppressed in JAM-C-deficient mice (JAM-C−/−) and enhanced in mice overexpressing JAM-C in their endothelial cells (ECs). Analysis of JAM-C subcellular expression by immunoelectron microscopy indicated that in I/R-injured tissues, EC JAM-C was redistributed from cytoplasmic vesicles and EC junctional sites to nonjunctional plasma membranes, a response that may account for the role of JAM-C in both leukocyte adhesion and transmigration under conditions of I/R injury.Conclusions—The findings demonstrate a role for EC JAM-C in mediating leukocyte adhesion and transmigration in response to I/R injury and indicate the existence of a novel regulatory mechanism for redistribution and hence function of EC JAM-C in vivo.
- Published
- 2009
48. Expression and Function of Junctional Adhesion Molecule-C in Myelinated Peripheral Nerves
- Author
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Beat A. Imhof, Peter J. Coffey, Rime Madani, Alexander Lobrinus, Ralf H. Adams, Dominique Ducrest-Gay, Richard Reynolds, Michel Aurrand-Lions, Dorothée Caille, Sussan Nourshargh, Yiangos Yiangou, Thomas E. Salt, Praveen Anand, Owain W. Howell, Alan S.L. Yu, Paolo Meda, and Christoph Scheiermann
- Subjects
Membrane Proteins/ metabolism ,education ,Neural Conduction ,Immunoglobulins ,Action Potentials ,Schwann cell ,ddc:616.07 ,Biology ,Nerve Fibers, Myelinated ,Cell junction ,Article ,Mice ,Immunolabeling ,Myelin ,Sural Nerve ,Peripheral Nerves/ metabolism/physiology ,medicine ,Animals ,Humans ,Peripheral Nerves ,Myelin Sheath ,Mice, Knockout ,Multidisciplinary ,Cell adhesion molecule ,Sural Nerve/metabolism/physiology ,fungi ,Cell Adhesion Molecules/ metabolism ,Membrane Proteins ,Peripheral Nervous System Diseases ,Schwann Cells/ metabolism ,Nerve Fibers, Myelinated/metabolism/ physiology/ultrastructure ,Anatomy ,Sciatic Nerve ,Intercellular Junctions/metabolism ,humanities ,Cell biology ,Myelin Sheath/metabolism/ physiology/ultrastructure ,Intercellular Junctions ,medicine.anatomical_structure ,nervous system ,Neuroglia ,Sciatic Nerve/metabolism/physiology/ultrastructure ,Schwann Cells ,Sciatic nerve ,Cell Adhesion Molecules ,Immunoglobulins/ metabolism ,Peripheral Nervous System Diseases/metabolism/pathology/physiopathology ,Junctional Adhesion Molecule C - Abstract
JAM-C is an adhesion molecule that is expressed on cells within the vascular compartment and epithelial cells and, to date, has been largely studied in the context of inflammatory events. Using immunolabeling procedures in conjunction with confocal and electron microscopy, we show here that JAM-C is also expressed in peripheral nerves and that this expression is localized to Schwann cells at junctions between adjoining myelin end loops. Sciatic nerves from JAM-C–deficient [having the JAM-C gene knocked out (KO)] mice exhibited loss of integrity of the myelin sheath and defective nerve conduction as indicated by morphological and electrophysiological studies, respectively. In addition, behavioral tests showed motor abnormalities in the KO animals. JAM-C was also expressed in human sural nerves with an expression profile similar to that seen in mice. These results demonstrate that JAM-C is a component of the autotypic junctional attachments of Schwann cells and plays an important role in maintaining the integrity and function of myelinated peripheral nerves.
- Published
- 2007
49. Neutrophil ageing is regulated by the microbiome
- Author
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Yuya Kunisaki, Jeremiah J. Faith, Jung Eun Jang, Dachuan Zhang, Chunliang Xu, Arthur Mortha, Robert D. Burk, Grace Chen, Miriam Merad, Deepa Manwani, Christoph Scheiermann, and Paul S. Frenette
- Subjects
Male ,Microbiota/immunology ,Macrophage-1 Antigen/metabolism ,Myeloid Differentiation Factor 88/metabolism ,Neutrophils ,Population ,Erythrocytes, Abnormal/pathology ,Erythrocytes, Abnormal ,Macrophage-1 Antigen ,Inflammation ,Anemia, Sickle Cell ,Biology ,CXCR4 ,Mice ,medicine ,Inflammation/immunology/pathology ,Animals ,Cellular Senescence/immunology ,education ,Toll-Like Receptors/immunology ,Cellular Senescence ,education.field_of_study ,Multidisciplinary ,Innate immune system ,Microbiota ,Shock, Septic/immunology/microbiology/pathology ,Toll-Like Receptors ,Neutrophil extracellular traps ,Shock, Septic ,Neutrophils/cytology/immunology ,Haematopoiesis ,Disease Models, Animal ,Macrophage-1 antigen ,Immunology ,Myeloid Differentiation Factor 88 ,medicine.symptom ,Anemia, Sickle Cell/blood/microbiology/pathology ,Cell aging ,Signal Transduction - Abstract
Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.
- Published
- 2015
50. Inflammatory leukocytes exhibit distinct rhythms in their recruitment to arteries and veins
- Author
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David Druzd, Christoph Scheiermann, Alba de Juan, and Kerstin Kraus
- Subjects
Rhythm ,business.industry ,Genetics ,Physiology ,Medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology ,Cause of death - Abstract
Acute cardiovascular complications occur predominantly at the onset of the behavioral activity phase and are the major cause of death in humans. Recent evidence points to a critical role for rhythm...
- Published
- 2015
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