المؤلفون: Kathrin Klee, Dagmar Schütz, Praveen Ashok Kumar, Thomas Ulas, Christoph Redecker, Friederike Saaber, Yves Werner, Frederic Geissmann, Amelie Lupp, Elvira Mass, Joachim L. Schultze, Kristian Händler, Ralf Stumm, Arik Horne

المصدر: Nature neuroscience 23(3), 351-362 (2020). doi:10.1038/s41593-020-0585-y
Nat Neurosci

مصطلحات موضوعية: immunology [Brain Ischemia], 0301 basic medicine, CXCR4 protein, mouse, pathology [Ischemic Attack, Transient], CXCR4, Monocytes, Brain Ischemia, 0302 clinical medicine, immunology [Ischemic Attack, Transient], Mice, Knockout, Microglia, General Neuroscience, pathology [Microglia], Cerebral Infarction, immunology [Microglia], Cell biology, Stroke, Haematopoiesis, Treatment Outcome, medicine.anatomical_structure, Ischemic Attack, Transient, medicine.symptom, Stem cell, immunology [Cerebral Infarction], Receptors, CXCR4, pathology [Hematopoietic Stem Cells], Inflammation, Biology, pathology [Brain Ischemia], Article, immunology [Monocytes], 03 medical and health sciences, Immune system, medicine, Animals, Cell Lineage, ddc:610, immunology [Hematopoietic Stem Cells], immunology [Receptors, CXCR4], Innate immune system, pathology [Monocytes], Monocyte, Thrombosis, Hematopoietic Stem Cells, Immunity, Innate, genetics [Receptors, CXCR4], pathology [Thrombosis], pathology [Cerebral Infarction], genetics [Immunity, Innate], Mice, Inbred C57BL, 030104 developmental biology, pathology [Stroke], metabolism [Receptors, CXCR4], Neuroscience, immunology [Stroke], 030217 neurology & neurosurgery

الوصف: Monocyte-derived and tissue-resident macrophages are ontogenetically distinct components of the innate immune system. Assessment of their respective functions in pathology is complicated by changes to the macrophage phenotype during inflammation. Here, we find that Cxcr4-CreER enables permanent genetic labeling of hematopoietic stem cells (HSCs) and distinguishes HSC-derived monocytes from microglia and other tissue-resident macrophages. By combining Cxcr4-CreER-mediated lineage tracing with Cxcr4 inhibition or conditional Cxcr4 ablation in photothrombotic stroke, we find that Cxcr4 promotes initial monocyte infiltration and subsequent territorial restriction of monocyte-derived macrophages to infarct tissue. After transient focal ischemia, Cxcr4-deficiency reduces monocyte infiltration and blunts the expression of pattern recognition and defense response genes in monocyte-derived macrophages. This is associated with an altered microglial response and deteriorated outcomes. Thus, Cxcr4 is essential for an innate immune-system-mediated defense response after cerebral ischemia. We further propose Cxcr4-CreER as a universal tool to study functions of HSC-derived cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af428157e8243870e5dce4666f5473e1Test
https://doi.org/10.1038/s41593-020-0585-yTest

المؤلفون: Adam Denes, Nicolai Franzmeier, Steffanie Heindl, Olga Carofiglio, Thomas Arzberger, Peter T. Nelson, Nikolett Lénárt, Alessio Ricci, Tibor Hortobágyi, Arthur Liesz, Dieter Edbauer, Qihui Zhou, Ann M. Stowe

المصدر: Journal of Experimental Medicine
Journal of experimental medicine 218(8), e20202411 (2021). doi:10.1084/jem.20202411
The Journal of Experimental Medicine

مصطلحات موضوعية: 0301 basic medicine, immunology [Brain Ischemia], Male, therapy [Stroke], Lymphocyte, Integrin alpha4, T-Lymphocytes, Autopsy, Brain Ischemia, immunology [T-Lymphocytes], 0302 clinical medicine, Neuroinflammation, pathology [Brain], drug effects [Neuronal Plasticity], Immunology and Allergy, immunology [Integrin alpha4], Stroke, Neuronal Plasticity, physiopathology [Stroke], biology, Natalizumab, Brain, Pathophysiology, 3. Good health, medicine.anatomical_structure, drug therapy [Brain Ischemia], immunology [Brain], Female, Immunotherapy, Antibody, drug effects [Recovery of Function], T cell, Immunology, pharmacology [Natalizumab], therapeutic use [Natalizumab], pathology [Brain Ischemia], 03 medical and health sciences, medicine, Animals, Humans, cardiovascular diseases, ddc:610, Lymphocyte Count, Cell Proliferation, business.industry, Brief Definitive Report, Recovery of Function, medicine.disease, Clinical trial, Mice, Inbred C57BL, 030104 developmental biology, biology.protein, business, 030217 neurology & neurosurgery, immunology [Stroke], Neuroscience

الوصف: Heindl et al. describe the local proliferation and clustering of T cells in the brain of mice and humans after stroke. This previously unrecognized phenomenon could explain why blocking cerebral leukocyte invasion might fail to improve long-term stroke recovery.
Neuroinflammation is an emerging focus of translational stroke research. Preclinical studies have demonstrated a critical role for brain-invading lymphocytes in post-stroke pathophysiology. Reducing cerebral lymphocyte invasion by anti-CD49d antibodies consistently improves outcome in the acute phase after experimental stroke models. However, clinical trials testing this approach failed to show efficacy in stroke patients for the chronic outcome 3 mo after stroke. Here, we identify a potential mechanistic reason for this phenomenon by detecting chronic T cell accumulation—evading the systemic therapy—in the post-ischemic brain. We observed a persistent accumulation of T cells in mice and human autopsy samples for more than 1 mo after stroke. Cerebral T cell accumulation in the post-ischemic brain was driven by increased local T cell proliferation rather than by T cell invasion. This observation urges re-evaluation of current immunotherapeutic approaches, which target circulating lymphocytes for promoting recovery after stroke.
Graphical Abstract

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f85b3077423c61350254debe6602a6adTest

المؤلفون: Joachim L. Schultze, Katarzyna Placek, Anna C. Aschenbrenner

المصدر: Journal of Clinical Investigation
J Clin Invest
The journal of clinical investigation 129(8), 2994-3005 (2019). doi:10.1172/JCI124619

مصطلحات موضوعية: 0301 basic medicine, immunology [Protein Processing, Post-Translational], Myocardial Infarction, immunology [Cellular Reprogramming], immunology [Histones], Chromatin remodeling, Epigenesis, Genetic, Histones, 03 medical and health sciences, immunology [Myocardial Infarction], 0302 clinical medicine, Immune system, immunology [Epigenesis, Genetic], Animals, Humans, ddc:610, Epigenetics, Epigenesis, biology, Review Series, pathology [Myocardial Infarction], epigenetics, injury, immune system, inflammation, General Medicine, DNA Methylation, Cellular Reprogramming, Cell biology, Stroke, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, DNA methylation, pathology [Stroke], biology.protein, Stem cell, Protein Processing, Post-Translational, Reprogramming, immunology [Stroke], immunology [DNA Methylation]

الوصف: Immune cells are pivotal in the reaction to injury, whereupon, under ideal conditions, repair and resolution phases restore homeostasis following initial acute inflammation. Immune cell activation and reprogramming require transcriptional changes that can only be initiated if epigenetic alterations occur. Recently, accelerated deciphering of epigenetic mechanisms has extended knowledge of epigenetic regulation, including long-distance chromatin remodeling, DNA methylation, posttranslational histone modifications, and involvement of small and long noncoding RNAs. Epigenetic changes have been linked to aspects of immune cell development, activation, and differentiation. Furthermore, genome-wide epigenetic landscapes have been established for some immune cells, including tissue-resident macrophages, and blood-derived cells including T cells. The epigenetic mechanisms underlying developmental steps from hematopoietic stem cells to fully differentiated immune cells led to development of epigenetic technologies and insights into general rules of epigenetic regulation. Compared with more advanced research areas, epigenetic reprogramming of immune cells in injury remains in its infancy. While the early epigenetic mechanisms supporting activation of the immune response to injury have been studied, less is known about resolution and repair phases and cell type-specific changes. We review prominent recent findings concerning injury-mediated epigenetic reprogramming, particularly in stroke and myocardial infarction. Lastly, we illustrate how single-cell technologies will be crucial to understanding epigenetic reprogramming in the complex sequential processes following injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3036ba638e8a12b1d3f0f9bfa779f18cTest

المؤلفون: Katarzyna Winek, Ulrich Dirnagl, Andreas Meisel

المصدر: Journal of cerebral blood flow & metabolism 36(5), 891-898 (2016). doi:10.1177/0271678X16636890

مصطلحات موضوعية: 0301 basic medicine, Future studies, Brief Opinion, Gut flora, Bioinformatics, immunology [Gastrointestinal Microbiome], immunology [Gastrointestinal Tract], 03 medical and health sciences, 0302 clinical medicine, Stroke outcome, Animals, Humans, ddc:610, Brain trauma, Brain function, biology, microbiology [Gastrointestinal Tract], Gastrointestinal Microbiome, biology.organism_classification, Gastrointestinal Tract, Stroke, 030104 developmental biology, Neurology, Blood-Brain Barrier, Neurology (clinical), metabolism [Blood-Brain Barrier], Cardiology and Cardiovascular Medicine, Neuroscience, immunology [Stroke], 030217 neurology & neurosurgery

الوصف: Microbiota and its contribution to brain function and diseases has become a hot topic in neuroscience. We discuss the emerging role of commensal bacteria in the course of stroke. Further, we review potential pitfalls in microbiota research and their impact on how we interpret the available evidence, emerging results, and on how we design future studies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d24fb4e278781f418a14d289946afd20Test
https://doi.org/10.1177/0271678x16636890Test

المؤلفون: Lalit Kaurani, Thomas Blank, Cemil Kerimoglu, Michael Gertig, Ori Staszewski, Jessica Wagner, Md. Rezaul Islam, Vincenzo Capece, Thomas Ulas, Matthias Staufenbiel, Andre Fischer, Mathias Jucker, Ann-Christin Wendeln, Katleen Wild, Marc Beyer, Jonas J. Neher, Tonatiuh Pena Centeno, Gaurav Jain, Joachim L. Schultze, Angelos Skodras, Karoline Degenhardt, Lisa M. Häsler, Marco Prinz, Moumita Datta

المصدر: Nature 556(7701), 332-338 (2018). doi:10.1038/s41586-018-0023-4
Nature

مصطلحات موضوعية: 0301 basic medicine, Male, animal diseases, metabolism [Microglia], Immune tolerance, Epigenesis, Genetic, pathology [Alzheimer Disease], Mice, immunology [Inflammation], pathology [Brain], immunology [Nervous System Diseases], Multidisciplinary, Microglia, Brain, Amyloidosis, immunology [Microglia], Stroke, medicine.anatomical_structure, immunology [Brain], Female, ddc:500, pathology [Amyloidosis], medicine.symptom, chemical and pharmacologic phenomena, Inflammation, Neuropathology, Article, 03 medical and health sciences, genetics [Inflammation], pathology [Nervous System Diseases], Immune system, Immunity, Alzheimer Disease, medicine, Immune Tolerance, Animals, Humans, Innate immune system, business.industry, immunology [Gene Expression Regulation], biochemical phenomena, metabolism, and nutrition, Immunity, Innate, immunology [Amyloidosis], immunology [Alzheimer Disease], Disease Models, Animal, 030104 developmental biology, Neuroimmunology, Gene Expression Regulation, pathology [Stroke], bacteria, Nervous System Diseases, business, Neuroscience, Immunologic Memory, immunology [Stroke]

الوصف: Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished—training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::33486403daa81ae9269ee406e0c46a46Test

المؤلفون: Klaus G. Reymann, Johannes Boltze, Alexander Kranz, Georg Reiser, David C. Hess, Daniel-Christoph Wagner

المساهمون: Publica

المصدر: Expert review of neurotherapeutics 11(2), 199-202 (2011). doi:10.1586/ern.10.202

مصطلحات موضوعية: therapy [Stroke], Microgliosis, Neuroprotection, Preclinical research, Animals, Humans, Regeneration, Medicine, Pharmacology (medical), ddc:610, Molecular Targeted Therapy, Translational Medical Research, Stroke, pharmacology [Neuroprotective Agents], business.industry, General Neuroscience, Metabolic Phenomena, medicine.disease, Magnetic Resonance Imaging, drug therapy [Stroke], Disease Models, Animal, Neuroprotective Agents, Research Design, Neurology (clinical), business, Neuroscience, immunology [Stroke], Stem Cell Transplantation

الوصف: Since 1998, the biannual International Symposium on Neuroprotection and Neurorepair, also known as the Magdeburg Meeting series, has provided a platform for the discussion of recent advances in basic and translational stroke research. The 2010 meeting reviewed highly relevant topics, including astrogliosis and microgliosis, neuroimmunological processes, cell-based therapies, novel imaging approaches, mechanisms of poststroke regeneration and metabolic phenomena in neuroprotection. It further focused on common pitfalls and opportunities in the translational process, from preclinical research to clinical application.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::81341f7ce377c33beae2110a7b8ebe80Test
https://doi.org/10.1586/ern.10.202Test

المؤلفون: Katarzyna Winek, Josef Priller, Andrey C. da Costa Goncalves, Claudia Dames, Christian Meisel, Mareike Thielke, Odilo Engel, Ulrich Dirnagl, Chotima Böttcher, Levent Akyüz, Hans-Dieter Volk, Susanne Herold, Andreas Meisel

المصدر: Stroke 46(11), 3232-3240 (2015). doi:10.1161/STROKEAHA.115.008989

مصطلحات موضوعية: Sympathetic nervous system, medicine.medical_treatment, microbiology [Pneumonia], Vagotomy, Receptors, Nicotinic, pharmacology [Benzamides], immunology [Macrophages, Alveolar], drug effects [Respiratory Mucosa], Parasympathetic nervous system, Mice, Heart Rate, Nicotinic Agonists, Chrna9 protein, mouse, Lung, pharmacology [Nicotinic Agonists], Mice, Knockout, immunology [Respiratory Mucosa], immunology [Parasympathetic Nervous System], drug effects [Parasympathetic Nervous System], Infarction, Middle Cerebral Artery, Stroke, medicine.anatomical_structure, Nicotinic agonist, drug effects [Macrophages, Alveolar], immunology [Pneumonia], Parasympathomimetics, Benzamides, drug effects [Heart Rate], immunology [Heart Rate], Cardiology and Cardiovascular Medicine, Bronchoalveolar Lavage Fluid, Acetylcholine, medicine.drug, Signal Transduction, genetics [Receptors, Nicotinic], Nicotine, immunology [Infarction, Middle Cerebral Artery], drug effects [Immunity, Innate], Respiratory Mucosa, PNU-282987, Bridged Bicyclo Compounds, Parasympathetic Nervous System, Macrophages, Alveolar, medicine, drug effects [Lung], Animals, microbiology [Bronchoalveolar Lavage Fluid], ddc:610, Cholinergic anti-inflammatory pathway, pharmacology [Bridged Bicyclo Compounds], Advanced and Specialized Nursing, immunology [Lung], business.industry, pharmacology [Nicotine], microbiology [Lung], Pneumonia, Immunity, Innate, immunology [Immunity, Innate], Mice, Inbred C57BL, Disease Models, Animal, immunology [Receptors, Nicotinic], Immunology, pharmacology [Parasympathomimetics], Cholinergic, Neurology (clinical), business, immunology [Stroke]

الوصف: Background and Purpose— Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. Methods— The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor–deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. Results— Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor–deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung. Conclusions— Thus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3519d5695d0e82d0b293000cf20e58fTest
https://pub.dzne.de/record/138198Test

المؤلفون: Jens Neumann, Monika Riek-Burchardt, Michael Görtler, Josephine Herz, Eloho Etemire, Peter Reichardt, Anika Klingberg, Thomas Fischer, Hans-Jochen Heinze, Klaus G. Reymann, Dirk M. Hermann, Matthias Gunzer, Thorsten R. Doeppner, Heiko Hütten, Rebecca König, Linda Männ, Burkhart Schraven

المصدر: Acta neuropathologica 129(2), 259-277 (2014). doi:10.1007/s00401-014-1355-2

مصطلحات موضوعية: immunology [Brain Ischemia], Male, physiology [Cell Adhesion], Pathology, Neutrophils, Medizin, Integrin alpha4beta1, immunology [Blood-Brain Barrier], metabolism [Integrin alpha4beta1], Brain Ischemia, Random Allocation, pathology [Brain], Medicine, pathology [Neutrophils], Microglia, pathology [Microglia], Brain, Stroke, physiology [Motor Activity], physiology [Neutrophils], medicine.anatomical_structure, Neutrophil Infiltration, Blood-Brain Barrier, immunology [Brain], medicine.symptom, Infiltration (medical), medicine.medical_specialty, Mice, Transgenic, Brain damage, Motor Activity, pathology [Brain Ischemia], Pathology and Forensic Medicine, Endothelial activation, Cellular and Molecular Neuroscience, Immune system, Mediator, Cell Adhesion, Animals, ddc:610, business.industry, VLA-4, pathology [Blood-Brain Barrier], Recovery of Function, medicine.disease, physiology [Microglia], Blockade, physiology [Neutrophil Infiltration], Mice, Inbred C57BL, Disease Models, Animal, physiology [Recovery of Function], Immunology, pathology [Stroke], Neurology (clinical), business, immunology [Stroke]

الوصف: Neuronal injury from ischemic stroke is aggravated by invading peripheral immune cells. Early infiltrates of neutrophil granulocytes and T-cells influence the outcome of stroke. So far, however, neither the timing nor the cellular dynamics of neutrophil entry, its consequences for the invaded brain area, or the relative importance of T-cells has been extensively studied in an intravital setting. Here, we have used intravital two-photon microscopy to document neutrophils and brain-resident microglia in mice after induction of experimental stroke. We demonstrated that neutrophils immediately rolled, firmly adhered, and transmigrated at sites of endothelial activation in stroke-affected brain areas. The ensuing neutrophil invasion was associated with local blood–brain barrier breakdown and infarct formation. Brain-resident microglia recognized both endothelial damage and neutrophil invasion. In a cooperative manner, they formed cytoplasmic processes to physically shield activated endothelia and trap infiltrating neutrophils. Interestingly, the systemic blockade of very-late-antigen-4 immediately and very effectively inhibited the endothelial interaction and brain entry of neutrophils. This treatment thereby strongly reduced the ischemic tissue injury and effectively protected the mice from stroke-associated behavioral impairment. Behavioral preservation was also equally well achieved with the antibody-mediated depletion of myeloid cells or specifically neutrophils. In contrast, T-cell depletion more effectively reduced the infarct volume without improving the behavioral performance. Thus, neutrophil invasion of the ischemic brain is rapid, massive, and a key mediator of functional impairment, while peripheral T-cells promote brain damage. Acutely depleting T-cells and inhibiting brain infiltration of neutrophils might, therefore, be a powerful early stroke treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d0dba94c5415b8ba8b8ed0ef46000417Test
https://pubmed.ncbi.nlm.nih.gov/25391494Test

المؤلفون: Emsley, H. C A, Smith, C. J., Georgiou, R. F., Vail, A., Barberan, E. M., Rothwell, N. J., Tyrrell, P. J., Hopkins, S. J., Waje-Andreassen, U., Kråkenes, J., Ulvestad, E., Thomassen, L., Myhr, K. M., Aarseth, J., Vedeler, C. A.

المصدر: Emsley , H C A , Smith , C J , Georgiou , R F , Vail , A , Barberan , E M , Rothwell , N J , Tyrrell , P J , Hopkins , S J , Waje-Andreassen , U , Kråkenes , J , Ulvestad , E , Thomassen , L , Myhr , K M , Aarseth , J & Vedeler , C A 2005 , ' Interleukin-6 and acute ischaemic stroke (multiple letters) ' , Acta Neurologica Scandinavica , vol. 112 , no. 4 , pp. 273-275 . https://doi.org/10.1111/j.1600-0404.2005.00479.xTest

مصطلحات موضوعية: Acute Disease, Biological Markers, immunology: Brain Ischemia, Humans, immunology: Interleukin-6, immunology: Stroke

الإتاحة: https://doi.org/10.1111/j.1600-0404.2005.00479.xTest
https://research.manchester.ac.uk/en/publications/c6f8459c-8363-44ba-a069-a08b73c99b9fTest