@article{RuckBittnerAfzalietal.2015, author = {Ruck, Tobias and Bittner, Stefan and Afzali, Ali Maisam and G{\"o}bel, Kerstin and Glumm, Sarah and Kraft, Peter and Sommer, Claudia and Kleinschnitz, Christoph and Preusse, Corinna and Stenzel, Werner and Wiendl, Heinz and Meuth, Sven G.}, title = {The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies}, series = {Oncotarget}, volume = {6}, journal = {Oncotarget}, number = {41}, doi = {10.18632/oncotarget.6462}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136047}, year = {2015}, abstract = {NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naive CD8\(^+\) T cells into highly activated, cytotoxic \(CD8^+NKG2D^{high}\) T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. \(CD8^+NKG2D^{high}\) T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68\(^+\) macrophages as well as CD4\(^+\) T cells, and \(CD8^+NKG2D^+\) cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues.}, language = {en} } @article{KornKleinschnitzMagnusetal.2016, author = {Korn, Thomas and Kleinschnitz, Christoph and Magnus, Tim and Meuth, Sven G. and Linker, Ralf A.}, title = {Report on the 7th scientific meeting of the Association for the Advancement of Young Academics in Neurology (NEUROWIND e.V.) held in Motzen, Germany, October 30-November 1, 2015}, series = {Experimental and Translational Stroke Medicine}, volume = {8}, journal = {Experimental and Translational Stroke Medicine}, number = {3}, organization = {7th NEUROWIND e.V. scientific meeting}, doi = {10.1186/s13231-016-0017-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146595}, year = {2016}, abstract = {From October 30-November 1, 2015, the 7th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Seventy doctoral students and postdocs from over 25 different groups working in German and Swiss University Hospitals or Research Institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. This meeting report summarizes the many diverse presentations and the new preclinical to clinical neurology research data that were shared by the participants at the meeting.}, language = {en} } @article{KleinschnitzLinkerMagnusetal.2015, author = {Kleinschnitz, Christoph and Linker, Ralf A. and Magnus, Tim and Korn, Thomas and Meuth, Sven G.}, title = {Report on the 6th scientific meeting of the "Verein zur F{\"o}rderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 31th - Nov. 2nd, 2014}, series = {Experimental \& Translational Stroke Medicine}, volume = {7}, journal = {Experimental \& Translational Stroke Medicine}, number = {1}, organization = {on behalf of the speakers at the 6'th NEUROWIND e.V. scientific meeting}, doi = {10.1186/s13231-014-0013-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125049}, year = {2015}, abstract = {From October 31th - November 2nd, 2014, the 6th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. 70 doctoral students and postdocs from over 25 different groups working in German and Swiss university hospitals or research institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. The meeting was regarded as a very well organized platform to support research of young investigators in Germany and all participants enjoyed the stimulating environment for lively in depth discussions. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 4th NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Michael Breckwoldt on his work in the group of Thomas Misgeld (Institute of Neuronal Cell Biology, Technische Universit{\"a}t M{\"u}nchen, Germany). The successful project was published in Nature Medicine entitled "Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo". This outstanding paper deals with a molecular imaging approach in living mice to optically analyze the role of mitochondrial redox signals in axons in health and disease. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year's keynote lecture was given by Bernhard Hemmer, Head of the Department of Neurology at the Klinikum rechts der Isar, Technische Universit{\"a}t M{\"u}nchen. Dr. Hemmer highlighted the particular role of B cells and (auto)antibodies in multiple sclerosis (MS). As a new highlight Dr. Urbahns, head of global discovery technologies at Merck research laboratories, gave insights from research practice in the pharmaceutical industry and introduced a shift in the view on present-day drug discovery paradigms.}, language = {en} } @article{LinkerMagnusKornetal.2013, author = {Linker, Ralf A. and Magnus, Tim and Korn, Thomas and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Report on the 5'th scientific meeting of the "Verein zur F{\"o}rderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 25th - Oct. 27th, 2013}, series = {Experimental \& Translational Stroke Medicine}, volume = {5}, journal = {Experimental \& Translational Stroke Medicine}, number = {15}, doi = {10.1186/2040-7378-5-15}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129230}, year = {2013}, abstract = {From october 25th - 27th 2013, the 5th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. This year more than 60 doctoral students and postdocs from over 25 different groups working in German university hospitals or research institutes attended the meeting to discuss their latest findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. All participants appreciated the stimulating environment in Motzen, Brandenburg, and people took the opportunity for scientific exchange, discussion about ongoing projects and already started further collaborations. Like in the previous years, the symposium was regarded as a very well organized platform to support research of young investigators in Germany. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 3rd NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Ruth Stassart working in the group of Klaus Armin Nave and Wolfgang Br{\"u}ck (MPI G{\"o}ttingen and Department of Neuropathology, G{\"o}ttingen Germany). The successful work was published in Nature Neuroscience entitled "A role for Swann cell-derived neuregulin-1 in remyelination". This outstanding paper deals with the function of Schwann cell neuregulin as an endogenous factor for myelin repair. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year's keynote lecture was given by Albert Ludolph, Head of the Department of Neurology at the University Clinic of Ulm. Dr. Ludolph highlighted the particular role of individual scientists for the development of research concepts in Alzheimer´s disease (AD) and frontotemporal dementia (FTD).}, language = {en} } @techreport{LinkerMeuthMagnusetal.2012, author = {Linker, Ralf, A. and Meuth, Sven G. and Magnus, Tim and Korn, Thomas and Kleinschnitz, Christoph}, title = {Report on the 4'th scientific meeting of the "Verein zur F{\"o}rderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 2'nd - Nov. 4'th, 2012 [meeting report]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76407}, year = {2012}, abstract = {From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year's keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of D{\"u}sseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012.}, subject = {Medizin}, language = {en} } @techreport{MagnusLinkerMeuthetal.2011, author = {Magnus, Tim and Linker, Ralf A. and Meuth, Sven G. and Kleinschnitz, Christoph and Korn, Thomas}, title = {Report on the 2nd scientific meeting of the "Verein zur Foerderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 29'th - Oct. 31'st, 2010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68789}, year = {2011}, abstract = {Summary of the scientific contributions to the NEUROWIND meeting 2010: Contributions in the fields of neuroimmunology and neurodegeneration}, subject = {Wissenschaftlicher Nachwuchs}, language = {en} } @article{KleinschnitzGrundWingleretal.2010, author = {Kleinschnitz, Christoph and Grund, Henrike and Wingler, Kirstin and Armitage, Melanie E. and Jones, Emma and Mittal, Manish and Barit, David and Schwarz, Tobias and Geis, Christian and Kraft, Peter and Barthel, Konstanze and Schuhmann, Michael K. and Herrmann, Alexander M. and Meuth, Sven G. and Stoll, Guido and Meurer, Sabine and Schrewe, Anja and Becker, Lore and Gailus-Durner, Valerie and Fuchs, Helmut and Klopstock, Thomas and de Angelis, Martin Hrabe and Jandeleit-Dahm, Karin and Shah, Ajay M. and Weissmann, Norbert and Schmidt, Harald H. H. W.}, title = {Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68416}, year = {2010}, abstract = {Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90\% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.}, subject = {Schlaganfall}, language = {en} } @article{RolfesRuckDavidetal.2022, author = {Rolfes, Leoni and Ruck, Tobias and David, Christina and Mencl, Stine and Bock, Stefanie and Schmidt, Mariella and Strecker, Jan-Kolja and Pfeuffer, Steffen and Mecklenbeck, Andreas-Schulte and Gross, Catharina and Gliem, Michael and Minnerup, Jens and Schuhmann, Michael K. and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Natural Killer Cells Are Present in Rag1\(^{-/-}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke}, series = {Translational Stroke Research}, volume = {13}, journal = {Translational Stroke Research}, number = {1}, issn = {1868-4483}, doi = {10.1007/s12975-021-00923-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308924}, pages = {197-211}, year = {2022}, abstract = {Rag1\(^{-/-}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{-/-}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{-/-}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{-/-}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{-/-}\) were comparable in number and function to those in WT mice. Rag1\(^{-/-}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1-/- controls. Our results indicate that NK cells from Rag1-/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.}, language = {en} } @article{EhlingGoebBittneretal.2013, author = {Ehling, Petra and G{\"o}b, Eva and Bittner, Stefan and Budde, Thomas and Ludwig, Andreas and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?}, series = {Experimental \& Translational Stroke Medicine}, volume = {5}, journal = {Experimental \& Translational Stroke Medicine}, number = {16}, doi = {10.1186/2040-7378-5-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131887}, year = {2013}, abstract = {Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing \(I_h\), stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55\%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model.}, language = {en} } @article{KleinschnitzGoebelMeuthetal.2014, author = {Kleinschnitz, Christoph and G{\"o}bel, Kerstin and Meuth, Sven G. and Kraft, Peter}, title = {Glatiramer acetate does not protect from acute ischemic stroke in mice}, doi = {10.1186/2040-7378-6-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110528}, year = {2014}, abstract = {Background The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis. Findings We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1. Conclusions Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia.}, language = {en} }