title: Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.
abstract: The blood-brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Shijie
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sonobe
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Horiuchi
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Bijay
authors.initials: B
authors.lastname: Parajuli
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kawanokuchi
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D019899:Paracrine Communication; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D018925:Chemokines; D053823:Hedgehog Proteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C465570:Shh protein, mouse