Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice

Daisuke Ibi, Taku Nagai, Akira Nakajima, Hiroyuki Mizoguchi, Takahiro Kawase, Daisuke Tsuboi, Shin Ichi Kano, Yoshiaki Sato, Masahiro Hayakawa, Ulrike C. Lange, David J. Adams, M. Azim Surani, Takaya Satoh, Akira Sawa, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada

研究成果: Article

32 引用 (Scopus)

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Interferon-induced transmembrane protein 3 (IFITM3) iplays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in longlasting neuronal impairments in mice following polyriboinosinic-polyribocytidylic acid (polyI:C, a synthetic double-stranded RNA)- induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C-treated astrocytes (polyI:C-ACM), neurite development was impaired. These polyI:CACM- induced neurodevelopmental abnormalities were alleviated by ifitm3-/- astrocyte-conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C-treated wild-type mice, but such neuronal impairments were not observed in ifitm3-/- mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.

元の言語English
ページ(範囲)679-693
ページ数15
ジャーナルGLIA
61
発行部数5
DOI
出版物ステータスPublished - 2013
外部発表Yes

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All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

これを引用

Ibi, D., Nagai, T., Nakajima, A., Mizoguchi, H., Kawase, T., Tsuboi, D., Kano, S. I., Sato, Y., Hayakawa, M., Lange, U. C., Adams, D. J., Surani, M. A., Satoh, T., Sawa, A., Kaibuchi, K., Nabeshima, T., & Yamada, K. (2013). Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. GLIA, 61(5), 679-693. https://doi.org/10.1002/glia.22461