Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation
Youichi Shinozaki,
Keisuke Shibata,
Keitaro Yoshida,
Eiji Shigetomi,
Christian Gachet,
Kazuhiro Ikenaka,
Kenji F. Tanaka,
Schuichi Koizumi
Affiliations
Youichi Shinozaki
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
Keisuke Shibata
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
Keitaro Yoshida
Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
Eiji Shigetomi
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
Christian Gachet
Institut National de la Santé et de la Recherche Médicale (INSERM), U.311, Etablissement de Transfusion Sanguine, 10, rue Spielmann, B.P. 36, 67065 Strasbourg, France
Kazuhiro Ikenaka
Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan
Kenji F. Tanaka
Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
Schuichi Koizumi
Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
Microglia and astrocytes become reactive following traumatic brain injury (TBI). However, the coordination of this reactivity and its relation to pathophysiology are unclear. Here, we show that microglia transform astrocytes into a neuroprotective phenotype via downregulation of the P2Y1 purinergic receptor. TBI initially caused microglial activation in the injury core, followed by reactive astrogliosis in the peri-injured region and formation of a neuroprotective astrocyte scar. Equivalent changes to astrocytes were observed in vitro after injury. This change in astrocyte phenotype resulted from P2Y1 receptor downregulation, mediated by microglia-derived cytokines. In mice, astrocyte-specific P2Y1 receptor overexpression (Astro-P2Y1OE) counteracted scar formation, while astrocyte-specific P2Y1 receptor knockdown (Astro-P2Y1KD) facilitated scar formation, suggesting critical roles of P2Y1 receptors in the transformation. Astro-P2Y1OE and Astro-P2Y1KD mice showed increased and reduced neuronal damage, respectively. Altogether, our findings indicate that microglia-astrocyte interaction, involving a purinergic signal, is essential for the formation of neuroprotective astrocytes.
