title: Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice.
abstract: Interferon-induced transmembrane protein 3 (IFITM3) ıplays 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 long-lasting 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:C-ACM-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.
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Daisuke
authors: D
authors: Ibi
authors: Taku
authors: T
authors: Nagai
authors: Akira
authors: A
authors: Nakajima
authors: Hiroyuki
authors: H
authors: Mizoguchi
authors: Takahiro
authors: T
authors: Kawase
authors: Daisuke
authors: D
authors: Tsuboi
authors: Shin-Ichi
authors: S
authors: Kano
authors: Yoshiaki
authors: Y
authors: Sato
authors: Masahiro
authors: M
authors: Hayakawa
authors: Ulrike C
authors: UC
authors: Lange
authors: David J
authors: DJ
authors: Adams
authors: M Azim
authors: MA
authors: Surani
authors: Takaya
authors: T
authors: Satoh
authors: Akira
authors: A
authors: Sawa
authors: Kozo
authors: K
authors: Kaibuchi
authors: Toshitaka
authors: T
authors: Nabeshima
authors: Kiyofumi
authors: K
authors: Yamada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000276:immunology / Q000473:pathology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology / Q000473:pathology*; D011070:Poly I-C / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; D012333:RNA, Messenger; C462181:fragilis protein, mouse; D011070:Poly I-C
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