Publication Date:
2012-04-25
Description:
Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1 -knockout ( Ppt1 -KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4 + T-helper 17 (T H 17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1 -KO mice, (ii) if so, do T H 17-lymphocytes underlie this complication, and (iii) how might T H 17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1 -KO mice and that T H 17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T H 17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1 -KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4 + T lymphocytes to IL-17A-positive T H 17 cells. Our findings uncover a mechanism by which T H 17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T H 17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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