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Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes

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 microglia...

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Autores principales: Wang, Yue, Jin, Shijie, Sonobe, Yoshifumi, Cheng, Yi, Horiuchi, Hiroshi, Parajuli, Bijay, Kawanokuchi, Jun, Mizuno, Tetsuya, Takeuchi, Hideyuki, Suzumura, Akio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196962/
https://www.ncbi.nlm.nih.gov/pubmed/25313834
http://dx.doi.org/10.1371/journal.pone.0110024
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author Wang, Yue
Jin, Shijie
Sonobe, Yoshifumi
Cheng, Yi
Horiuchi, Hiroshi
Parajuli, Bijay
Kawanokuchi, Jun
Mizuno, Tetsuya
Takeuchi, Hideyuki
Suzumura, Akio
author_facet Wang, Yue
Jin, Shijie
Sonobe, Yoshifumi
Cheng, Yi
Horiuchi, Hiroshi
Parajuli, Bijay
Kawanokuchi, Jun
Mizuno, Tetsuya
Takeuchi, Hideyuki
Suzumura, Akio
author_sort Wang, Yue
collection PubMed
description 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.
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spelling pubmed-41969622014-10-16 Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes Wang, Yue Jin, Shijie Sonobe, Yoshifumi Cheng, Yi Horiuchi, Hiroshi Parajuli, Bijay Kawanokuchi, Jun Mizuno, Tetsuya Takeuchi, Hideyuki Suzumura, Akio PLoS One Research Article 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. Public Library of Science 2014-10-14 /pmc/articles/PMC4196962/ /pubmed/25313834 http://dx.doi.org/10.1371/journal.pone.0110024 Text en © 2014 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wang, Yue
Jin, Shijie
Sonobe, Yoshifumi
Cheng, Yi
Horiuchi, Hiroshi
Parajuli, Bijay
Kawanokuchi, Jun
Mizuno, Tetsuya
Takeuchi, Hideyuki
Suzumura, Akio
Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
title Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
title_full Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
title_fullStr Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
title_full_unstemmed Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
title_short Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
title_sort interleukin-1β induces blood–brain barrier disruption by downregulating sonic hedgehog in astrocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196962/
https://www.ncbi.nlm.nih.gov/pubmed/25313834
http://dx.doi.org/10.1371/journal.pone.0110024
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