title: CX3CR1 RNAi inhibits hypoxia-induced microglia activation via p38MAPK/PKC pathway.
abstract: 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 CX3CR1. However, the specific mechanisms involved in fractalkine/CX3CR1-mediated microglial activation have not been fully identified. In the present study, we constructed lentivirus encoding shRNA against CX3CR1 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 CX3CR1 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 p38MAPK/PKC activation. Therefore, our results reveal a novel mechanism of fractalkine/CX3CR1 involvement in activation of microglia. Thus CX3CR1 RNAi might provide a therapeutic strategy which could be useful in chronic cerebral ischaemia.
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Zhao
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.forename: Qianning
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000073883:CX3C Chemokine Receptor 1; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D054428:Chemokine CX3CL1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D034622:RNA Interference; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D053583:Interleukin-1beta; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2
keywords: CX3CR1; RNAi; hypoxi; microglia; p38MAPK/PKC