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Anne Ladwig [1] and Helene Luise Walter [1] and Jörg Hucklenbroich [1] and Antje Willuweit [2] and Karl-Josef Langen [2] and Gereon Rudolph Fink [1; 3] and Maria Adele Rueger [1; 3] and Michael Schroeter [1; 3]

Academic Editor: Michal A. Rahat

1, Department of Neurology, University Hospital of Cologne, Cologne, Germany, uk-koeln.de

2, Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Research Centre Juelich, Juelich, Germany

3, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Juelich, Germany

Received Jun 7, 2017; Revised Jul 30, 2017; Accepted Aug 29, 2017

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Focal cerebral ischemia induces an activation of brain resident glial cells and an influx of peripheral immune cells [1]. Those inflammatory responses have been termed a “double-edged sword” since they not only serve beneficial functions, such as phagocytosis of debris and recruitment of neural stem cells, but also mediate secondary tissue damage [2]. Multiple activational states of microglia are often coined in a dichotomous way as M1 and M2 subtypes, with more proinflammatory and detrimental effects attributed to the M1 phenotype while more regulatory and protective actions attributed to M2 phenotypes [3]. We previously characterized the process by which microglia as the resident immune cells of the brain separate vital brain tissue from ischemic necrosis [4]. At the very margin of those two, the “demarcation zone” is characterized by microglia actively secreting the nerve/glial antigen 2 (NG2) into the extracellular matrix (ECM), thereby separating necrosis from vital tissue with a decisive impact on secondary tissue damage [4]. Recently, Gliem et al. reported the ECM glycoprotein osteopontin (OPN) to be involved in the demarcation of focal ischemic lesions by elongating astrocytic processes, improving astrocyte-mediated neovessel coverage [5]. Our own recent work revealed direct effects of OPN on primary microglia in vitro, promoting their survival while shifting their inflammatory profile towards a more neutral phenotype [6]. Although exact protein concentrations are unknown, OPN protein is virtually absent in the naïve brain, but OPN mRNA is upregulated by some 5000 times in the infarct area after focal cerebral ischemia. The absence...

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