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.
Highlights
The blood–brain barrier (BBB) is a tight seal composed of capillary endothelial cells, pericytes, and perivascular astrocytes [1]
Treatment with IL-1b alone significantly increased the permeability of BBB, and conditioned media from IL-1b–stimulated astrocytes lost the ability to increase BBB integrity (Fig. 1). These findings suggested that IL-1b disrupts BBB integrity directly, and indirectly via astrocyte dysfunction
IL-1b decreased astrocytic production of Sonic hedgehog (SHH) we focused on SHH, a soluble factor released from astrocytes that plays an important role in BBB maintenance
Summary
The blood–brain barrier (BBB) is a tight seal composed of capillary endothelial cells, pericytes, and perivascular astrocytes [1]. Disruption of BBB integrity is frequently observed in neurologic diseases such as multiple sclerosis (MS), Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease, suggesting that infiltrating molecules and immune cells from the blood perturb CNS homeostasis and exacerbate these disorders [8,9,10,11,12,13]. Microglial activation is another characteristic pathologic feature in these diseases [14]. Our findings reveal novel mechanisms of BBB disruption by IL-1b, and suggest that SHH could be used therapeutically against various neurologic diseases
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