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Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus

Susanne A. Wolf^*,,1, Barbara Steiner^*,||,#, Antje Wengner, Martin Lipp, Thomas Kammertoens^,¶ and Gerd Kempermann^*,||,2

^* Neuronal Stem Cells Research Group,

Molecular Tumor Genetics Research Group, and

Molecular Immunology and Genetherapy Research Group, Max Delbrück Centre for Molecular Medicine, Berlin-Buch, Germany;

Institute of Biological Sciences, Institute of Neurosurgery, Stanford University, Stanford, CA, USA;

^|| Volkswagenstiftung Research Group, Department of Experimental Neurology, and

^¶ Institutes of Immunology, Charité, Berlin, Germany; and

^# Department of Neurology, Charité University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany

² Correspondence: CRTD-DFG-Center for Regenerative Therapies Dresden, Tatzberg 47-49, 01307 Dresden, Germany. E-mail: gerd.kempermann{at}crt-dresden.de

To understand the link between peripheral immune activation and neuronal precursor biology, we investigated the effect of T-cell activation on adult hippocampal neurogenesis in female C57Bl/6 mice. A peripheral adaptive immune response triggered by adjuvant-induced rheumatoid arthritis (2 µg/µl methylated BSA) or staphylococcus enterotoxin B (EC₅₀ of 0.25 µg/ml per 20 g body weight) was associated with a transient increase in hippocampal precursor cell proliferation and neurogenesis as assessed by immunohistochemistry and confocal microscopy. Both treatments were paralleled by an increase in corticosterone levels in the hippocampus 1- to 2-fold over the physiological amount measured by quantitative radioimmunoassay. In contrast, intraperitoneal administration of the innate immune response activator lipopolysaccaride (EC₅₀ of 0.5 µg/ml per 20 g body weight) led to a chronic 5-fold increase of hippocampal glucocorticoid levels and a decrease of adult neurogenesis. In vitro exposure of murine neuronal progenitor cells to corticosterone triggered either cell death at high (1.5 nM) or proliferation at low (0.25 nM) concentrations. This effect could be blocked using a viral vector system expressing a transdomain of the glucocorticoid receptor. We suggest an evolutionary relevant communication route for the brain to respond to environmental stressors like inflammation mediated by glucocorticoid levels in the hippocampus.—Wolf, S. A., Steiner, B., Wengner, A., Lipp, M., Kammertoens, T., Kempermann, G. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus.

Key Words: CD4 • glucocorticoids • rheumatoid arthritis