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Interactions between chemokines: regulation of fractalkine/CX3CL1 homeostasis by SDF/CXCL12 in cortical neurons
Journal article   Open access   Peer reviewed

Interactions between chemokines: regulation of fractalkine/CX3CL1 homeostasis by SDF/CXCL12 in cortical neurons

Anna Cook, Randi Hippensteel, Saori Shimizu, Jaclyn Nicolai, Alessandro Fatatis and Olimpia Meucci
The Journal of biological chemistry, v 285(14), pp 10563-10571
02 Apr 2010
DOI: https://doi.org/10.1074/jbc.M109.035477
PMID: 20124406
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1074/jbc.M109.035477View
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Abstract

ADAM17 Protein Chemokine CX3CL1 - metabolism Homeostasis Neurons - cytology RNA, Messenger - metabolism Cerebral Cortex - cytology Cerebral Cortex - metabolism Embryo, Mammalian - metabolism N-Methylaspartate - pharmacology Neuroglia - drug effects Neuroglia - cytology Chemokine CXCL12 - genetics Neurons - metabolism Cerebral Cortex - drug effects Neurons - drug effects ADAM Proteins - antagonists & inhibitors Enzyme-Linked Immunosorbent Assay RNA, Messenger - genetics Cells, Cultured ADAM10 Protein Rats Chemokine CX3CL1 - genetics Reverse Transcriptase Polymerase Chain Reaction Blotting, Western ADAM Proteins - metabolism Amyloid Precursor Protein Secretases - metabolism Animals Chemokine CXCL12 - metabolism Embryo, Mammalian - cytology Neuroglia - metabolism Amyloid Precursor Protein Secretases - antagonists & inhibitors
The soluble form of the chemokine fractalkine/CX(3)CL1 regulates microglia activation in the central nervous system (CNS), ultimately affecting neuronal survival. This study aims to determine whether CXCL12, another chemokine constitutively expressed in the CNS (known as stromal cell-derived factor 1; SDF-1), regulates cleavage of fractalkine from neurons. To this end, ELISA was used to measure protein levels of soluble fractalkine in the medium of rat neuronal cultures exposed to SDF-1. Gene arrays, quantitative RT-PCR, and Western blot were used to measure overall fractalkine expression in neurons. The data show that the rate of fractalkine shedding in healthy cultures positively correlates with in vitro differentiation and survival. In analogy to non-neuronal cells, metalloproteinases (ADAM10/17) are involved in cleavage of neuronal fractalkine as indicated by studies with pharmacologic inhibitors. Moreover, treatment of the neuronal cultures with SDF-1 stimulates expression of the inducible metalloproteinase ADAM17 and increases soluble fractalkine content in culture medium. The effect of SDF-1 is blocked by an inhibitor of both ADAM10 and -17, but only partially affected by a more specific inhibitor of ADAM10. In addition, SDF-1 also up-regulates expression of the fractalkine gene. Conversely, exposure of neurons to an excitotoxic stimulus (i.e. NMDA) inhibits alpha-secretase activity and markedly diminishes soluble fractalkine levels, leading to cell death. These results, along with previous findings on the neuroprotective role of both SDF-1 and fractalkine, suggest that this novel interaction between the two chemokines may contribute to in vivo regulation of neuronal survival by modulating microglial neurotoxic properties.

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Web of Science research areas
Biochemistry & Molecular Biology
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