@article{DuettingGaitsIacovoniStegneretal.2017,
  author    = {D{\"u}tting, Sebastian and Gaits-Iacovoni, Frederique and Stegner, David and Popp, Michael and Antkowiak, Adrien and van Eeuwijk, Judith M.M. and Nurden, Paquita and Stritt, Simon and Heib, Tobias and Aurbach, Katja and Angay, Oguzhan and Cherpokova, Deya and Heinz, Niels and Baig, Ayesha A. and Gorelashvili, Maximilian G. and Gerner, Frank and Heinze, Katrin G. and Ware, Jerry and Krohne, Georg and Ruggeri, Zaverio M. and Nurden, Alan T. and Schulze, Harald and Modlich, Ute and Pleines, Irina and Brakebusch, Cord and Nieswandt, Bernhard},
  title     = {A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis},
  series = {Nature Communications},
  volume    = {8},
  journal   = {Nature Communications},
  number    = {15838},
  doi       = {10.1038/ncomms15838},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170797},
  year      = {2017},
  abstract  = {Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard-Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V.},
  language  = {en}
}
@article{GilPulidoCochainLippertetal.2017,
  author    = {Gil-Pulido, Jesus and Cochain, Clement and Lippert, Malte A. and Schneider, Nicole and Butt, Elke and Am{\´e}zaga, N{\´u}ria and Zernecke, Alma},
  title     = {Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0181947},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170535},
  pages     = {e0181947},
  year      = {2017},
  abstract  = {Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α\(^{+}\) and CD103\(^{+}\) DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr\(^{-/-}\))-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α\(^{+}\) and CD103\(^{+}\) antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis.},
  language  = {en}
}
@article{LeopoldZeilbeckWeberetal.2017,
  author    = {Leopold, Stephanie A. and Zeilbeck, Ludwig F. and Weber, Gregor and Seitz, Roswitha and B{\"o}sl, Michael R. and J{\"a}gle, Herbert and Fuchshofer, Rudolf and Tamm, Ernst R. and Ohlmann, Andreas},
  title     = {Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-017-14423-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173494},
  year      = {2017},
  abstract  = {Norrin is a secreted signaling molecule activating the Wnt/β-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a β-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/β-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.},
  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{StegnervanEeuwijkAngayetal.2017,
  author    = {Stegner, David and van Eeuwijk, Judith M.M. and Angay, Oğuzhan and Gorelashvili, Maximilian G. and Semeniak, Daniela and Pinnecker, J{\"u}rgen and Schmithausen, Patrick and Meyer, Imke and Friedrich, Mike and D{\"u}tting, Sebastian and Brede, Christian and Beilhack, Andreas and Schulze, Harald and Nieswandt, Bernhard and Heinze, Katrin G.},
  title     = {Thrombopoiesis is spatially regulated by the bone marrow vasculature},
  series = {Nature Communications},
  volume    = {8},
  journal   = {Nature Communications},
  number    = {127},
  doi       = {10.1038/s41467-017-00201-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170591},
  year      = {2017},
  abstract  = {In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts.},
  language  = {en}
}