Activity of adenosine receptors type 1 Is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons
Open accessAbstract
The chemokine fractalkine (CX(3)CL1) is constitutively expressed by central neurons, regulating microglial responses including chemotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX(3)CR1, CX(3)CL1 exerts both neuroprotection against glutamate (Glu) toxicity and neuromodulation of the glutamatergic synaptic transmission in hippocampal neurons. Using cultured hippocampal neuronal cell preparations, obtained from CX(3)CR1(-/-) (CX(3)CR1(GFP/GFP)) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX(3)CL1-treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX(3)CL1-induced neuroprotection from Glu toxicity is mediated through the adenosine receptor 1 (AR(1)), being blocked by neuronal cell preparations treatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a specific inhibitor of AR(1), and mimicked by both adenosine and the specific AR(1) agonist 2-chloro-N(6)-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX(3)CR1(+/+) mice, show that CX(3)CL1-induced depression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- (AMPA-) type Glu receptor-mediated current (AMPA-current), is associated with AR(1) activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPA-current depression in CX(3)CR1(GFP/GFP) hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX(3)CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX(3)CL1, along with AR(1), are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR(1) mediates neuromodulatory action of CX(3)CL1 on hippocampal neurons.
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- Authors
- Lauro, C., Di Angelantonio, S., Cipriani, R., Sobrero, F., Antonilli, L., Brusadin, V., Ragozzino, D., & Limatola, C.
- Affiliations
- Istituto Pasteur (IT)
- Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza BEMM, Università Sapienza , Roma
- University of Bari Aldo Moro (IT)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-06-01
- Volume
- 180
- Issue
- 11
- Pages
- 7590-7596
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1546864953
- Cited by
- 110
- References
- 48
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 1 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 8 · 2013: 13 · 2012: 8
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- fractalkine, CX3CR1, neuroprotection, glutamate excitotoxicity, AMPA receptors, hippocampal neurons, microglia, adenosine release, neuromodulation, DPCPX, 2-chloro-N6-cyclopentyladenosine, chemokine signaling
- MeSH terms
- Animals, Cell Line, Cells, Cultured, Hippocampus, Mice, Mutant Strains, Neurons, Xanthines, Receptors, Purinergic P1, Receptors, AMPA, Neuroprotective Agents, Mice, Rats, Chemokine CX3CL1, Purinergic P1 Receptor Antagonists
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