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Microglia–blood vessel interactions: a double-edged sword in brain pathologies

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Abstract

Microglia are long-living resident immune cells of the brain, which secure a stable chemical and physical microenvironment necessary for the proper functioning of the central nervous system (CNS). These highly dynamic cells continuously scan their environment for pathogens and possess the ability to react to damage-induced signals in order to protect the brain. Microglia, together with endothelial cells (ECs), pericytes and astrocytes, form the functional blood–brain barrier (BBB), a specialized endothelial structure that selectively separates the sensitive brain parenchyma from blood circulation. Microglia are in bidirectional and permanent communication with ECs and their perivascular localization enables them to survey the influx of blood-borne components into the CNS. Furthermore, they may stimulate the opening of the BBB, extravasation of leukocytes and angiogenesis. However, microglia functioning requires tight control as their dysregulation is implicated in the initiation and progression of numerous neurological diseases. Disruption of the BBB, changes in blood flow, introduction of pathogens in the sensitive CNS niche, insufficient nutrient supply, and abnormal secretion of cytokines or expression of endothelial receptors are reported to prime and attract microglia. Such reactive microglia have been reported to even escalate the damage of the brain parenchyma as is the case in ischemic injuries, brain tumors, multiple sclerosis, Alzheimer's and Parkinson's disease. In this review, we present the current state of the art of the causes and mechanisms of pathological interactions between microglia and blood vessels and explore the possibilities of targeting those dysfunctional interactions for the development of future therapeutics.

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Acknowledgments

We thank Darragh O'Neill for proofreading the manuscript.

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    Authors and Affiliations

    1. Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany

      Nevenka Dudvarski Stankovic, Marcin Teodorczyk & Mirko H. H. Schmidt

    2. German Cancer Consortium (DKTK), Heidelberg, Germany

      Nevenka Dudvarski Stankovic & Mirko H. H. Schmidt

    3. German Cancer Research Center (DKFZ), Heidelberg, Germany

      Nevenka Dudvarski Stankovic & Mirko H. H. Schmidt

    4. Department of Neurology, Focus Program Translational Neuroscience (FTN) and Research Center for Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University, Mainz, Germany

      Robert Ploen & Frauke Zipp

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    1. Nevenka Dudvarski Stankovic
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    Correspondence to Mirko H. H. Schmidt.

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    This work was supported by a grant of the German Academic Exchange Service (DAAD) to NDS, the German Research Foundation (DFG) via the collaborative research center 1080, projects A3 (MHHS) and B6 (FZ), the DFG Grant SCHM 2159/2-1 to MHHS and by a German Cancer Consortium (DKTK) grant to NDS and MHHS.

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    N. Dudvarski Stankovic and M. Teodorczyk contributed equally to this work.

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    Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R. et al. Microglia–blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol 131, 347–363 (2016). https://doi.org/10.1007/s00401-015-1524-y

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