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

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)679-693
Number of pages15
JournalGLIA
Volume61
Issue number5
DOIs
Publication statusPublished - 2013

Fingerprint

Astrocytes
Interferons
Proteins
Conditioned Culture Medium
Brain
Interferon Type I
Double-Stranded RNA
Endosomes
Frontal Lobe
Neurites
Dendrites
Endocytosis
Nervous System Diseases
Antiviral Agents
Immune System
Spine
Central Nervous System
Cytokines
Neurons
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Ibi, D., Nagai, T., Nakajima, A., Mizoguchi, H., Kawase, T., Tsuboi, D., ... 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
Ibi, Daisuke ; Nagai, Taku ; Nakajima, Akira ; Mizoguchi, Hiroyuki ; Kawase, Takahiro ; Tsuboi, Daisuke ; Kano, Shin Ichi ; Sato, Yoshiaki ; Hayakawa, Masahiro ; Lange, Ulrike C. ; Adams, David J. ; Surani, M. Azim ; Satoh, Takaya ; Sawa, Akira ; Kaibuchi, Kozo ; Nabeshima, Toshitaka ; Yamada, Kiyofumi. / Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. In: GLIA. 2013 ; Vol. 61, No. 5. pp. 679-693.
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abstract = "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.",
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Ibi, D, Nagai, T, Nakajima, A, Mizoguchi, H, Kawase, T, Tsuboi, D, Kano, SI, Sato, Y, Hayakawa, M, Lange, UC, Adams, DJ, Surani, MA, Satoh, T, Sawa, A, Kaibuchi, K, Nabeshima, T & Yamada, K 2013, 'Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice', GLIA, vol. 61, no. 5, pp. 679-693. https://doi.org/10.1002/glia.22461

Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. / Ibi, Daisuke; Nagai, Taku; Nakajima, Akira; Mizoguchi, Hiroyuki; Kawase, Takahiro; Tsuboi, Daisuke; Kano, Shin Ichi; Sato, Yoshiaki; Hayakawa, Masahiro; Lange, Ulrike C.; Adams, David J.; Surani, M. Azim; Satoh, Takaya; Sawa, Akira; Kaibuchi, Kozo; Nabeshima, Toshitaka; Yamada, Kiyofumi.

In: GLIA, Vol. 61, No. 5, 2013, p. 679-693.

Research output: Contribution to journalArticle

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AU - Ibi, Daisuke

AU - Nagai, Taku

AU - Nakajima, Akira

AU - Mizoguchi, Hiroyuki

AU - Kawase, Takahiro

AU - Tsuboi, Daisuke

AU - Kano, Shin Ichi

AU - Sato, Yoshiaki

AU - Hayakawa, Masahiro

AU - Lange, Ulrike C.

AU - Adams, David J.

AU - Surani, M. Azim

AU - Satoh, Takaya

AU - Sawa, Akira

AU - Kaibuchi, Kozo

AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

PY - 2013

Y1 - 2013

N2 - 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.

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Ibi D, Nagai T, Nakajima A, Mizoguchi H, Kawase T, Tsuboi D et al. Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. GLIA. 2013;61(5):679-693. https://doi.org/10.1002/glia.22461