期刊
PLOS ONE
卷 6, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0025016
关键词
-
资金
- Public Health Service [R56-AI40635, R01-NS047599]
- Saban Research Institute
- National Natural Science Foundation of China [81070514]
Alpha7 nicotinic acetylcholine receptor (nAChR), an essential regulator of inflammation, is abundantly expressed in hippocampal neurons, which are vulnerable to bacterial meningitis. However, it is unknown whether 7 nAChR contributes to the regulation of these events. In this report, an aggravating role of alpha 7 nAChR in host defense against meningitic E. coli infection was demonstrated by using alpha 7-deficient (alpha 7(-/-)) mouse brain microvascular endothelial cells (BMEC) and animal model systems. As shown in our in vitro and in vivo studies, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the blood-brain barrier (BBB) were significantly reduced in alpha 7(-/-) BMEC and alpha 7(-/-) mice. Stimulation by nicotine was abolished in the alpha 7(-/-) cells and animals. The same blocking effect was achieved by methyllycaconitine (alpha 7 antagonist). The tight junction molecules occludin and ZO-1 were significantly reduced in the brain cortex of wildtype mice infected with E. coli and treated with nicotine, compared to alpha 7(-/-) cells and animals. Decreased neuronal injury in the hippocampal dentate gyrus was observed in alpha 7(-/-) mice with meningitis. Proinflammatory cytokines (IL-1 beta, IL-6, TNF alpha, MCP-1, MIP-1alpha, and RANTES) and adhesion molecules (CD44 and ICAM-1) were significantly reduced in the cerebrospinal fluids of the alpha 7(-/-) mice with E. coli meningitis. Furthermore, alpha 7 nAChR is the major calcium channel for nicotine-and E. coli K1-increased intracellular calcium concentrations of mouse BMEC. Taken together, our data suggest that alpha 7 nAChR plays a detrimental role in the host defense against meningitic infection by modulation of pathogen invasion, PMN recruitment, calcium signaling and neuronal inflammation.
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