CX 3 CR 1 RNA i inhibits hypoxia‐induced microglia activation via p38 MAPK / PKC pathway

Summary There is accumulating evidence which demonstrates that chronic cerebral ischaemia can induce white matter lesions ( WML s), 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 CX 3 CR 1. However, the specific mechanisms involved in fractalkine/ CX 3 CR 1‐mediated microglial activation have not been fully identified. In the present study, we constructed lentivirus encoding sh RNA against CX 3 CR 1 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 CX 3 CR 1 RNA i‐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/ CX 3 CR 1 involvement in activation of microglia. Thus CX 3 CR 1 RNA i might provide a therapeutic strategy which could be useful in chronic cerebral ischaemia.