title: High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression.
abstract: Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1-TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Takizawa
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shibata
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kayama
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Toriumi
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Ebine
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Unekawa
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Anri
authors.initials: A
authors.lastname: Koh
authors.affiliation: 2 Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: 1 Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D013181:Cortical Spreading Depression; D024243:HMGB1 Protein / Q000502:physiology*; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D024243:HMGB1 Protein; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D002402:Cathepsin D; C533923:Ctsd protein, mouse
keywords: Toll-like receptors; cathepsin D; cortical spreading depression; high-mobility group box 1; microglia