title: Plexin-A1 is required for Toll-like receptor-mediated microglial activation in the development of lipopolysaccharide-induced encephalopathy.
abstract: Recent investigations have suggested that semaphorins, which are known repulsive axon guidance molecules, may play a crucial role in maintaining brain homeostasis by regulating microglial activity. Sema3A, secreted in higher amounts from injured neurons, is considered to suppress excessive inflammatory responses by inducing microglial apoptosis through its binding to Plexin-A1 receptors on activated microglia. To clarify the in vivo role of Plexin-A1-mediated signaling in lipopolysaccharide (LPS)-induced injury in mouse brain, we examined the neuroinflammatory changes initiated by LPS administration to the cerebral ventricles of wild-type (WT) and Plexin-A1-deficient (-/-) mice. WT mice administered LPS exhibited a significantly higher expression of COX-2, iNOS, IL-1β and TNF-α in the hippocampus, and a significantly greater ventricular enlargement and intracerebral infiltration of leukocytes, as compared with the saline-treated group. By contrast, Plexin-A1-/- mice administered LPS did not exhibit a significantly increased expression of COX-2, iNOS, IL-1β or TNF-α in the hippocampus as compared with the saline-treated group. Plexin-A1-/- mice administered LPS did not show significant increases in ventricle size or infiltration of leukocytes into the brain, as compared with the saline-treated group. In WT, but not in the Plexin-A1-/- primary microglia treated with LPS, Sema3A induced significantly more nitric oxide production than in the immunoglobulin G control. These results revealed the crucial role of the Sema3A-Plexin-A1 interaction in the Toll-like receptor 4-mediated signaling of the LPS-induced activation of microglia. Thus, results of the present study revealed the essential role of Plexin-A1 in the development of LPS-induced neuroinflammation in mice, suggesting the possible application of microglial control of the semaphorin-plexin signaling system to the treatment of LPS-induced encephalopathy and other psychiatric diseases associated with neuroinflammation.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.affiliation: Laboratory Animal Center, Wakayama Medical University, Wakayama 641-8509, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.affiliation: Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.affiliation: Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2