Title

Ischemia-induced Neuronal Cell Death Is Mediated by Chemokine Receptor CX3CR1

Document Type

Article

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.

Medical Subject Headings

Animals; Apoptosis; CX3C Chemokine Receptor 1 (genetics, metabolism); Calcium (metabolism); Cells, Cultured; Corpus Striatum (metabolism, pathology); Glutamic Acid (toxicity); Hippocampus (metabolism, pathology); Infarction, Middle Cerebral Artery (metabolism); Male; Mice; Mice, Inbred C57BL; Neurons (drug effects, metabolism); Up-Regulation

Publication Date

1-11-2018

Publication Title

Scientific reports

E-ISSN

2045-2322

Volume

8

Issue

1

First Page

556

PubMed ID

29323156

Digital Object Identifier (DOI)

10.1038/s41598-017-18774-0

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