Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death.
Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-alpha, interleukin-1-beta, and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A(1) receptors (A(1)R) with the specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) abolishes CX3CL1-mediated rescue of neuronal excitotoxic death and that CX3CL1 induces the release of adenosine from microglia. In this study, we show that the presence of extracellular adenosine is mandatory for the neurotrophic effect of CX3CL1 as reducing adenosine levels in hippocampal cultures, by adenosine deaminase treatment, strongly impairs CX3CL1-mediated neuroprotection. Furthermore, we confirm the predominant role of microglia in mediating the neuronal effects of CX3CL1, because the selective depletion of microglia from hippocampal cultures treated with clodronate-filled liposomes causes the complete loss of effect of CX3CL1. We also show that hippocampal neurons obtained from A(1)R(-/-) mice are not protected by CX3CL1 whereas A(2A)R(-/-) neurons are. The requirement of functional A(1)R for neuroprotection is not unique for CX3CL1 as A(1)R(-/-) hippocampal neurons are not rescued from Glu-induced cell death by other neurotrophins such as brain-derived neurotrophic factor and erythropoietin, which are fully active on wt neurons.
Lauro
Clotilde
C
Istituto Pasteur, Fondazione Cenci Bolognetti, Rome, Italy.
Cipriani
Raffaela
R
Catalano
Myriam
M
Trettel
Flavia
F
Chece
Giuseppina
G
Brusadin
Valentina
V
Antonilli
Letizia
L
van Rooijen
Nico
N
Eusebi
Fabrizio
F
Fredholm
Bertil B
BB
Limatola
Cristina
C
D000241:Adenosine / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists; D000243:Adenosine Deaminase / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D000073883:CX3C Chemokine Receptor 1; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000737:chemistry / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D009924:Organ Culture Techniques; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000172:deficiency; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D019208:Brain-Derived Neurotrophic Factor; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D019707:Receptors, Chemokine; D014970:Xanthines; D004002:Clodronic Acid; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D004921:Erythropoietin; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000243:Adenosine Deaminase; D000241:Adenosine