Abstract
The chemokine fractalkine (CX3CL1) and its receptor CX3CR1 play a fundamental role in the pathophysiology of stroke. Previous studies have focused on a paracrine interaction between neurons that produce fractalkine and microglia that express CX3CR1 receptors in the central nervous system. Recent findings have demonstrated the functional expression of CX3CR1 receptors by hippocampal neurons, suggesting their involvement in neuroprotective and neurodegenerative actions. To elucidate the roles of neuronal CX3CR1 in neurodegeneration induced by ischemic stroke, a mouse model of permanent middle cerebral artery occlusion (pMCAO) was employed. In the pMCAO mice, increased CX3CR1 levels, apoptosis-associated morphological changes, and Caspase 3-positive neuronal cells were observed in the striatum and in the hippocampus 24 hours after occlusion. Upregulation of CX3CR1 in ischemic neurons is associated with neuronal apoptotic cell death. In contrast, ischemia-induced apoptotic neuronal cell death was decreased in CX3CR1 deficient mice. Cultured primary hippocampal neurons obtained from CX3CR1 deficient mice were more resistant to glutamate-induced excitotoxicity by blocking calcium influx than those from wild-type mice. For the first time, we reported that neuronal CXCR1 mediates neuronal apoptotic cell death in ischemia. Our results suggest that modulating CXCR1 activity offers a novel therapeutic strategy for stroke.
Highlights
The chemokine fractalkine (CX3CL1)/CX3C chemokine receptor 1 (CX3CR1) system has been shown to play an important role in modulating the communication between neurons and resident microglia in the central nervous system (CNS)[4,5,6]
Our principal findings are: (1) CX3CR1 is unregulated in ischemic neurons in vitro and in a mouse model of permanent focal ischemia; (2) neuronal CX3CR1 elevation is associated with apoptotic neuronal death; (3) CX3CR1 deficiency protects mice from ischemic brain damage in vivo; (4) CX3CR1 deficiency reduces glutamate-mediated excitotoxicity in hippocampal neurons cultured in vitro with a mechanism dependent on
Based on the previous observation that CX3CR1 receptors are exclusively found on microglia and astrocytes[6,10], we and others had focused on the microglia-neuron communication via CX3CL1/CX3CR1 signaling
Summary
The chemokine fractalkine (CX3CL1)/CX3C chemokine receptor 1 (CX3CR1) system has been shown to play an important role in modulating the communication between neurons and resident microglia in the central nervous system (CNS)[4,5,6]. It has been previously reported that CX3CR1 deficiency is associated with decreased neuronal apoptosis and improved outcomes following ischemic brain injury[7,8]. Meucci et al recently provided direct evidence for the functional expression of CX3CR1 receptors by hippocampal neurons and demonstrated their involvement in the neuroprotective action of fractalkine[11]. We hypothesized that CX3CR1 directly mediates brain ischemia-induced neuronal apoptosis. We report that CX3CR1 is upregulated in ischemic neurons in mice subjected to focal cerebral ischemia. Higher levels of CX3CR1 are associated with apoptotic neuronal death, and calcium influx plays a crucial role in this process of cell death. ® CX3CR1 expression was evaluated by calculating the mean density with the VisionWorks LS Image Acquisition and Analysis Software (UVP, LLC, CA, USA)
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