title: The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS.
abstract: The brain-blood barrier (BBB) tightly limits immune cell migration into the central nervous system (CNS), avoiding unwanted inflammation under the normal state. However, immune cells can traverse the BBB when inflammation occurs within the CNS, suggesting a certain signal that creates a gateway that bypasses the BBB might exist. We revealed the inflammation amplifier as a mechanism of this signal, and identified dorsal vessels of the fifth lumber (L5) spinal cord as the gateway. The inflammation amplifier is driven by a simultaneous activation of NF-κB and STATs in non-immune cells, causing the production of a large amount of inflammatory chemokines to open the gateway at L5 vessels. It was found that the activation of the amplifier can be modulated by neural activation and artificially operated by electric pulses followed by establishment of new gateways, Gateway Reflex, at least in mice. Furthermore, genes required for the inflammation amplifier have been identified and are highly associated with various inflammatory diseases and disorders in the CNS. Thus, physical and/or pharmacological manipulation of the inflammation amplifier holds therapeutic value to control neuro-inflammation.
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Lavannya
authors.initials: L
authors.lastname: Sabharwal
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Bando
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ogura
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Nakayama
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Jiang
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Kumai
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Arima
authors.affiliation: Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan murakami@igm.hokudai.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D012018:Reflex / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D013116:Spinal Cord / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D018925:Chemokines; D050791:STAT Transcription Factors
keywords: Gateway reflex; NF-κB; STAT; blood–brain barrier; inflammation amplifier