@article{SchuhmannLanghauserKraftetal.2017,
  author    = {Schuhmann, Michael K. and Langhauser, Friederike and Kraft, Peter and Kleinschnitz, Christoph},
  title     = {B cells do not have a major pathophysiologic role in acute ischemic stroke in mice},
  series = {Journal of Neuroinflammation},
  volume    = {14},
  journal   = {Journal of Neuroinflammation},
  number    = {112},
  doi       = {10.1186/s12974-017-0890-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158155},
  year      = {2017},
  abstract  = {Background Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. Methods Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD\(^{-/-}\) mice and Rag1\(^{-/-}\) mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. Results Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD\(^{-/-}\) mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1\(^{-/-}\) mice with B cells had no influence on infarct volumes. Conclusion Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke.},
  language  = {en}
}
@article{BieberSchuhmannBellutetal.2022,
  author    = {Bieber, Michael and Schuhmann, Michael K. and Bellut, Maximilian and Stegner, David and Heinze, Katrin G. and Pham, Mirko and Nieswandt, Bernhard and Stoll, Guido},
  title     = {Blockade of platelet glycoprotein Ibα augments neuroprotection in Orai2-deficient mice during middle cerebral artery occlusion},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {16},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23169496},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286038},
  year      = {2022},
  abstract  = {During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte-platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2\(^{-/-}\)) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα-von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2\(^{-/-}\) mice. During ischemia-reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2\(^{-/-}\) mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke.},
  language  = {en}
}
@article{SchuhmannGuthmannStolletal.2017,
  author    = {Schuhmann, Michael K. and Guthmann, Josua and Stoll, Guido and Nieswandt, Bernhard and Kraft, Peter and Kleinschnitz, Christoph},
  title     = {Blocking of platelet glycoprotein receptor Ib reduces "thrombo-inflammation" in mice with acute ischemic stroke},
  series = {Journal of Neuroinflammation},
  volume    = {14},
  journal   = {Journal of Neuroinflammation},
  number    = {18},
  doi       = {10.1186/s12974-017-0792-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157582},
  year      = {2017},
  abstract  = {Background: Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Methods: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Results: Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. Conclusion: In acute ischemic stroke, thrombus formation and inflammation are closely intertwined ("thrombo-inflammation"). Blocking of platelet GPIb can ameliorate thrombo-inflammation.},
  language  = {en}
}
@article{GoebelPankratzAsaridouetal.2016,
  author    = {G{\"o}bel, Kerstin and Pankratz, Susann and Asaridou, Chloi-Magdalini and Herrmann, Alexander M. and Bittner, Stefan and Merker, Monika and Ruck, Tobias and Glumm, Sarah and Langhauser, Friederike and Kraft, Peter and Krug, Thorsten F. and Breuer, Johanna and Herold, Martin and Gross, Catharina C. and Beckmann, Denise and Korb-Pap, Adelheid and Schuhmann, Michael K. and Kuerten, Stefanie and Mitroulis, Ioannis and Ruppert, Clemens and Nolte, Marc W. and Panousis, Con and Klotz, Luisa and Kehrel, Beate and Korn, Thomas and Langer, Harald F. and Pap, Thomas and Nieswandt, Bernhard and Wiendl, Heinz and Chavakis, Triantafyllos and Kleinschnitz, Christoph and Meuth, Sven G.},
  title     = {Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  number    = {11626},
  doi       = {10.1038/ncomms11626},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165503},
  year      = {2016},
  abstract  = {Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.},
  language  = {en}
}
@article{AlbertWeissenbergerMenclSchuhmannetal.2014,
  author    = {Albert-Weissenberger, Christiane and Mencl, Stine and Schuhmann, Michael K. and Salur, Irmak and G{\"o}b, Eva and Langhauser, Friederike and Hopp, Sarah and Hennig, Nelli and Meuth, Sven G. and Nolte, Marc W. and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph},
  title     = {C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00269},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119263},
  pages     = {269},
  year      = {2014},
  abstract  = {Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75\% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.},
  language  = {en}
}
@article{KraftSchuhmann2022,
  author    = {Kraft, Peter and Schuhmann, Michael K.},
  title     = {Cellular and molecular targets in acute ischemic stroke},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {19},
  issn      = {1422-0067},
  doi       = {10.3390/ijms231911097},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288294},
  year      = {2022},
  abstract  = {No abstract available},
  language  = {en}
}
@article{KraftDrechslerSchuhmannetal.2015,
  author    = {Kraft, Peter and Drechsler, Christiane and Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph},
  title     = {Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {International Journal of Molecular Science},
  volume    = {16},
  journal   = {International Journal of Molecular Science},
  number    = {10},
  doi       = {10.3390/ijms161025433},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126319},
  pages     = {25433-25449},
  year      = {2015},
  abstract  = {Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital W{\"u}rzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies.},
  language  = {en}
}
@article{KraemerSchuhmannVolkmannetal.2022,
  author    = {Kr{\"a}mer, Stefanie D. and Schuhmann, Michael K. and Volkmann, Jens and Fluri, Felix},
  title     = {Deep brain stimulation in the subthalamic nucleus can improve skilled Forelimb movements and retune dynamics of striatal networks in a rat stroke model},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {24},
  doi       = {10.3390/ijms232415862},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312828},
  year      = {2022},
  abstract  = {Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in rats on forelimb grasping using the single-pellet reaching (SPR) test after stroke and determined costimulated brain regions during STN-HFS using 2-[\(^{18}\)F]Fluoro-2-deoxyglucose-([\(^{18}\)F]FDG)-positron emission tomography (PET). After a 4-week training of SPR, photothrombotic stroke was induced in the sensorimotor cortex of the dominant hemisphere. Thereafter, an electrode was implanted in the STN ipsilateral to the infarction, followed by a continuous STN-HFS or sham stimulation for 7 days. On postinterventional day 2 and 7, an SPR test was performed during STN-HFS. Success rate of grasping was compared between these two time points. [\(^{18}\)F]FDG-PET was conducted on day 2 and 3 after stroke, without and with STN-HFS, respectively. STN-HFS resulted in a significant improvement of SPR compared to sham stimulation. During STN-HFS, a significantly higher [\(^{18}\)F]FDG-uptake was observed in the corticosubthalamic/pallidosubthalamic circuit, particularly ipsilateral to the stimulated side. Additionally, STN-HFS led to an increased glucose metabolism within the brainstem. These data demonstrate that STN-HFS supports rehabilitation of skilled forelimb movements, probably by retuning dysfunctional motor centers within the cerebral network.},
  language  = {en}
}
@article{BellutBieberKraftetal.2023,
  author    = {Bellut, Maximilian and Bieber, Michael and Kraft, Peter and Weber, Alexander N. R. and Stoll, Guido and Schuhmann, Michael K.},
  title     = {Delayed NLRP3 inflammasome inhibition ameliorates subacute stroke progression in mice},
  series = {Journal of Neuroinflammation},
  volume    = {20},
  journal   = {Journal of Neuroinflammation},
  number    = {1},
  doi       = {10.1186/s12974-022-02674-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300599},
  year      = {2023},
  abstract  = {Background Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke. Methods Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO. Results Infarct sizes on day 7 after tMCAO decreased about 35\% after delayed and about 60\% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis. Conclusions Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.},
  language  = {en}
}
@article{SchuhmannLanghauserZimmermannetal.2023,
  author    = {Schuhmann, Michael K. and Langhauser, Friederike and Zimmermann, Lena and Bellut, Maximilian and Kleinschnitz, Christoph and Fluri, Felix},
  title     = {Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke},
  series = {International journal of molecular sciences},
  volume    = {24},
  journal   = {International journal of molecular sciences},
  number    = {21},
  doi       = {10.3390/ijms242115540},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357731},
  year      = {2023},
  abstract  = {Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.},
  language  = {en}
}