title: Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain.
abstract: Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shichita
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hasegawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.forename: Ryota
authors.initials: R
authors.lastname: Sakaguchi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekiya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ooboshi
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagawa
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Hideo
authors.initials: H
authors.lastname: Takahashi
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Kuroda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology; D002545:Brain Ischemia / Q000150:complications*; D004660:Encephalitis / Q000209:etiology*; D024243:HMGB1 Protein / Q000502:physiology; D053759:Interleukin-23 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054464:Peroxiredoxins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D024243:HMGB1 Protein; D053759:Interleukin-23; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D054464:Peroxiredoxins