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Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.

Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

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.

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IL-1β downregulates SHH production in astrocytes.(A) Shh mRNA levels in astrocytes, determined by qPCR. Astrocytes were treated with IL-1β for 6 h. Values are means ± SEM (n = 5). *, p<0.05; †, p<0.01. (B) Protein levels of SHH in ACM, determined using ELISA. Astrocytes were treated with IL-1β for 24 h. Values are means ± SEM (n = 5). *, p<0.001.
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pone-0110024-g002: IL-1β downregulates SHH production in astrocytes.(A) Shh mRNA levels in astrocytes, determined by qPCR. Astrocytes were treated with IL-1β for 6 h. Values are means ± SEM (n = 5). *, p<0.05; †, p<0.01. (B) Protein levels of SHH in ACM, determined using ELISA. Astrocytes were treated with IL-1β for 24 h. Values are means ± SEM (n = 5). *, p<0.001.

Mentions: Next, we focused on SHH, a soluble factor released from astrocytes that plays an important role in BBB maintenance. Specifically, we investigated whether IL-1β affects astrocytic SHH expression. Treatment with IL-1β significantly decreased Shh mRNA levels in astrocytes in a dose-dependent manner (Fig. 2A). Similar results were obtained for SHH protein levels in ACM using specific ELISA (Fig. 2B).


Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.

Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A - PLoS ONE (2014)

IL-1β downregulates SHH production in astrocytes.(A) Shh mRNA levels in astrocytes, determined by qPCR. Astrocytes were treated with IL-1β for 6 h. Values are means ± SEM (n = 5). *, p<0.05; †, p<0.01. (B) Protein levels of SHH in ACM, determined using ELISA. Astrocytes were treated with IL-1β for 24 h. Values are means ± SEM (n = 5). *, p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196962&req=5

pone-0110024-g002: IL-1β downregulates SHH production in astrocytes.(A) Shh mRNA levels in astrocytes, determined by qPCR. Astrocytes were treated with IL-1β for 6 h. Values are means ± SEM (n = 5). *, p<0.05; †, p<0.01. (B) Protein levels of SHH in ACM, determined using ELISA. Astrocytes were treated with IL-1β for 24 h. Values are means ± SEM (n = 5). *, p<0.001.
Mentions: Next, we focused on SHH, a soluble factor released from astrocytes that plays an important role in BBB maintenance. Specifically, we investigated whether IL-1β affects astrocytic SHH expression. Treatment with IL-1β significantly decreased Shh mRNA levels in astrocytes in a dose-dependent manner (Fig. 2A). Similar results were obtained for SHH protein levels in ACM using specific ELISA (Fig. 2B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

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.

Show MeSH
Related in: MedlinePlus