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

Lu YM, Tao RR, Huang JY, Li LT, Liao MH, Li XM, Fukunaga K, Hong ZH, Han F - J Neuroinflammation (2012)

Bottom Line: 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 P2X(7).Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X(7)(-/-) mice compared with wild-type littermates following microsphere embolism insult.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, China.

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 P2X(7)-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 P2X(7)/FasL signaling. The BV-2 cells and primary microglia from mice genetically deficient in P2X(7) 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, P2X(7) 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 P2X(7). 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 P2X(7). Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X(7)(-/-) 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 P2X(7)-dependent mechanism. The specific modulation of P2X(7)/FasL signaling and aberrant microglial activation could provide therapeutic benefits in acute and subacute phase of cerebral microembolic injury.

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Schematic illustration of the hypothesis of the FasL-mediated cell death by focal microglia activation via P2X7receptors during microsphere embolism.
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Figure 10: Schematic illustration of the hypothesis of the FasL-mediated cell death by focal microglia activation via P2X7receptors during microsphere embolism.

Mentions: Based on our observations, the present study used the cerebral microemboli model and an in vitro culture system to provide further evidence of a role for microglial activation and P2X7/FasL-Fas signaling following ischemic insult. We demonstrate a new role for FasL in cerebral microvascular occlusion-mediated inflammatory responses and a previously unknown P2X7-based mechanism. In particular, these results also describe a mechanism that immunoreactive response loop of microglia-derived FasL further exaggerates P2X7-mediated microglial activation and triggers a vicious cycle of neuronal cell death in the ischemic context (Figure 10). The present results highlight the potential for a novel therapeutic neuroprotective approach using pharmacological blockade of sustained microglial activation and the death-inducing ligand in the acute and subacute phase of ischemia.


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

Lu YM, Tao RR, Huang JY, Li LT, Liao MH, Li XM, Fukunaga K, Hong ZH, Han F - J Neuroinflammation (2012)

Schematic illustration of the hypothesis of the FasL-mediated cell death by focal microglia activation via P2X7receptors during microsphere embolism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3420259&req=5

Figure 10: Schematic illustration of the hypothesis of the FasL-mediated cell death by focal microglia activation via P2X7receptors during microsphere embolism.
Mentions: Based on our observations, the present study used the cerebral microemboli model and an in vitro culture system to provide further evidence of a role for microglial activation and P2X7/FasL-Fas signaling following ischemic insult. We demonstrate a new role for FasL in cerebral microvascular occlusion-mediated inflammatory responses and a previously unknown P2X7-based mechanism. In particular, these results also describe a mechanism that immunoreactive response loop of microglia-derived FasL further exaggerates P2X7-mediated microglial activation and triggers a vicious cycle of neuronal cell death in the ischemic context (Figure 10). The present results highlight the potential for a novel therapeutic neuroprotective approach using pharmacological blockade of sustained microglial activation and the death-inducing ligand in the acute and subacute phase of ischemia.

Bottom Line: 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 P2X(7).Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X(7)(-/-) mice compared with wild-type littermates following microsphere embolism insult.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, China.

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 P2X(7)-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 P2X(7)/FasL signaling. The BV-2 cells and primary microglia from mice genetically deficient in P2X(7) 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, P2X(7) 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 P2X(7). 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 P2X(7). Finally, the degrees of FasL overproduction and neuronal death were consistently reduced in P2X(7)(-/-) 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 P2X(7)-dependent mechanism. The specific modulation of P2X(7)/FasL signaling and aberrant microglial activation could provide therapeutic benefits in acute and subacute phase of cerebral microembolic injury.

Show MeSH
Related in: MedlinePlus