Microglia P2Y(13) Receptors Prevent Astrocyte Proliferation Mediated by P2Y(1) Receptors

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Clara Quintas (Author) FFUP; Nuno Vale (Author) ICBAS; Goncalves, J (Author) Other; Queiroz, G (Author) FFUP

Journal

Title: Frontiers in Pharmacology

Vol. 9

ISSN: 1663-9812

Publisher: Frontiers Media

Indexing

ISI Web of Knowledge - 35 Citations

Scopus - 35 Citations

Other information

Authenticus ID: P-00N-XV6

DOI: 10.3389/fphar.2018.00418

Abstract (EN): Cerebral inflammation is a common feature of several neurodegenerative diseases that requires a fine interplay between astrocytes and microglia to acquire appropriate phenotypes for an efficient response to neuronal damage. During brain inflammation, ATP is massively released into the extracellular medium and converted into ADP. Both nucleotides acting on P2 receptors, modulate astrogliosis through mechanisms involving microglia-astrocytes communication. In previous studies, primary cultures of astrocytes and co-cultures of astrocytes and microglia were used to investigate the influence of microglia on astroglial proliferation induced by ADP beta S, a stable ADP analog. In astrocyte cultures, ADPOS increased cell proliferation through activation of P2Y(1) and P2Y(12) receptors, an effect abolished in co-cultures (of astrocytes with similar to 12.5% microglia). The possibility that the loss of the ADP beta S-mediated effect could have been caused by a microglia-induced degradation of ADP beta S or by a preferential microglial localization of P2Y(1) or P2Y(12) receptors was excluded. Since ADP beta S also activates P2Y(13) receptors, the contribution of microglial P2Y(13) receptors to prevent the proliferative effect of ADP beta S in co-cultures was investigated. The results obtained indicate that P2Y(13) receptors are low expressed in astrocytes and mainly expressed in microglia. Furthermore, in co-cultures, ADP beta S induced astroglial proliferation in the presence of the selective P2Y(13) antagonist MRS 2211 (3 mu M) and of the selective P2Y(12) antagonist AR-C66096 (0.1 mu M), suggesting that activation of microglial P2Y(12) and P2Y(13) receptors may induce the release of messengers that inhibit astroglial proliferation mediated by P2Y(1)(,12) receptors. In this microglia-astrocyte paracrine communication, P2Y(12) receptors exert opposite effects in astroglial proliferation as a result of its cellular localization: cooperating in astrocytes with P2Y(1) receptors to directly stimulate proliferation and in microglia with P2Y(13) receptors to prevent proliferation. IL-1 beta also attenuated the proliferative effect of ADP beta S in astrocyte cultures. However, in co-cultures, the anti-IL-1 beta antibody was unable to recover the ADP beta S-proliferative effect, an effect that was achieved by the anti-IL-1 alpha and anti-TNF-alpha antibodies. It is concluded that microglia control the P2Y(1)(,12) receptor-mediated astroglial proliferation through a P2Y(12)(,13) receptormediated mechanism alternative to the IL-1 beta suppressive pathway that may involve the contribution of the cytokines IL-1 alpha and TNF-alpha.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12