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Microglia inflict delayed brain injury after subarachnoid hemorrhage

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Abstract

Inflammatory changes have been postulated to contribute to secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH). In human specimens after SAH as well as in experimental SAH using mice, we show an intracerebral accumulation of inflammatory cells between days 4 and 28 after the bleeding. Using bone marrow chimeric mice allowing tracing of all peripherally derived immune cells, we confirm a truly CNS-intrinsic, microglial origin of these immune cells, exhibiting an inflammatory state, and rule out invasion of myeloid cells from the periphery into the brain. Furthermore, we detect secondary neuro-axonal injury throughout the time course of SAH. Since neuronal cell death and microglia accumulation follow a similar time course, we addressed whether the occurrence of activated microglia and neuro-axonal injury upon SAH are causally linked by depleting microglia in vivo. Given that the amount of neuronal cell death was significantly reduced after microglia depletion, we conclude that microglia accumulation inflicts secondary brain injury after SAH.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (SFB TRR 43 and NeuroCure Exc 257 to FLH and PV, as well as HE 3130/6-1 to FLH) and the Federal Ministry of Education and Research (DLR/BMBF; Kompetenznetz Degenerative Demenzen to FLH). We thank Dr. Jana Glumm and Dr. Kelly Miller for kindly providing GFP-mice and CD11b-HSVTK mice, respectively. We thank Melina Nieminen-Kelhä and Irina Kremenetskaia for their constant technical support in the lab. We thank Adnan Ghori for advice in PCR issues.

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The authors have declared that no conflict of interest exists.

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Authors and Affiliations

  1. Department of Neurosurgery, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Ulf C. Schneider, Anja-Maria Davids, Tobias Finger & Peter Vajkoczy

  2. Experimental Neurosurgery, Charité, Universitätsmedizin Berlin, Berlin, Germany

    Ulf C. Schneider, Anja-Maria Davids, Susan Brandenburg, Annett Müller, Anna Elke, Salima Magrini, Etienne Atangana, Kati Turkowski, Tobias Finger & Peter Vajkoczy

  3. Department of Neurosurgery, Universitätsmedizin Göttingen, Göttingen, Germany

    Etienne Atangana & Angelika Gutenberg

  4. Institute of Neuropathology, Universitätsmedizin Göttingen, Göttingen, Germany

    Wolfgang Brück

  5. Department of Neuropathology, Charité, Universitätsmedizin Berlin, Berlin, Germany

    Claire Gehlhaar & Frank L. Heppner

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  1. Ulf C. Schneider
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Schneider, U.C., Davids, AM., Brandenburg, S. et al. Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol 130, 215–231 (2015). https://doi.org/10.1007/s00401-015-1440-1

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