Search

There is accumulating evidence which demonstrates that chronic cerebral ischaemia can induce white matter lesions ( WMLs), and microglia-activation-mediated cytokines and proteases releasing during the ischaemia might play a vital role in pathogenesis. In addition, hypoxia-induced upregulated expression of fractalkine promotes the activation of microglia and their migration to the lesions through interaction with its receptor CX3 CR1. However, the specific mechanisms involved in fractalkine/ CX3 CR1-mediated microglial activation have not been fully identified. In the present study, we constructed lentivirus encoding sh RNA against CX3 CR1 and transduced into microglial cells in under hypoxic conditions. Moreover, we analysed the proliferation, cytokine secretion and signal-pathway activation of the microglia. We found that CX3 CR1 RNAi-mediated gene downregulation could attenuate hypoxic-induced microglial proliferation, cytokine secretion [including tumuor necrosis factor-α ( TNF-α), interleukin-1β ( IL-1β)] and matrix metalloproteinase-2 ( MMP-2) synthesis. These effects were shown to be nediated through p38 MAPK/ PKC activation. Therefore, our results reveal a novel mechanism of fractalkine/ CX3 CR1 involvement in activation of microglia. Thus CX3 CR1 RNAi might provide a therapeutic strategy which could be useful in chronic cerebral ischaemia. [ABSTRACT FROM AUTHOR]