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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

P2X7 signaling promotes microsphere embolism-triggered microglia activation by maintaining elevation of Fas ligand

Authors: Ying-mei Lu, Rong-rong Tao, Ji-yun Huang, Li-tao Li, Mei-hua Liao, Xiao-ming Li, Kohji Fukunaga, Ze-Hui Hong, Feng Han

Published in: Journal of Neuroinflammation | Issue 1/2012

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Abstract

Background

The cerebral microvascular occlusion elicits microvascular injury which mimics the different degrees of stroke severity observed in patients, but the mechanisms underlying these embolic injuries are far from understood. The Fas ligand (FasL)-Fas system has been implicated in a number of pathogenic states. Here, we examined the contribution of microglia-derived FasL to brain inflammatory injury, with a focus on the potential to suppress the FasL increase by inhibition of the P2X7-FasL signaling with pharmacological or genetic approaches during ischemia.

Methods

The cerebral microvascular occlusion was induced by microsphere injection in experimental animals. Morphological changes in microglial cells were studied immunohistochemically. The biochemical analyses were used to examine the intracellular changes of P2X7/FasL signaling. The BV-2 cells and primary microglia from mice genetically deficient in P2X7 were used to further establish a linkage between microglia activation and FasL overproduction.

Results

The FasL expression was continuously elevated and was spatiotemporally related to microglia activation following microsphere embolism. Notably, P2X7 expression concomitantly increased in microglia and presented a distribution pattern that was similar to that of FasL in ED1-positive cells at pathological process of microsphere embolism. Interestingly, FasL generation in cultured microglia cells subjected to oxygen-glucose deprivation-treated neuron-conditioned medium was prevented by the silencing of P2X7. Furthermore, FasL induced the migration of BV-2 microglia, whereas the neutralization of FasL with a blocking antibody was highly effective in inhibiting ischemia-induced microglial mobility. Similar results were observed in primary microglia from wild-type mice or mice genetically deficient in P2X7. Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X7 −/− mice compared with wild-type littermates following microsphere embolism insult.

Conclusion

FasL functions as a key component of an immunoreactive response loop by recruiting microglia to the lesion sites through a P2X7-dependent mechanism. The specific modulation of P2X7/FasL signaling and aberrant microglial activation could provide therapeutic benefits in acute and subacute phase of cerebral microembolic injury.
Appendix
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Metadata
Title
P2X7 signaling promotes microsphere embolism-triggered microglia activation by maintaining elevation of Fas ligand
Authors
Ying-mei Lu
Rong-rong Tao
Ji-yun Huang
Li-tao Li
Mei-hua Liao
Xiao-ming Li
Kohji Fukunaga
Ze-Hui Hong
Feng Han
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-172

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