The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation

The disturbances of cellular proteostasis caused by the alteration in the ubiquitin‐proteasome system (UPS) have been proposed as a common mechanism underlying several neural pathologies that involve a neuro‐inflammatory process. As we have previously reported that the nucleotide receptor P2Y purinoceptor 2 (P2Y 2 R) regulates the proteasomal catalytic activities, we wonder whether this receptor is involved in the UPS disturbances associated with the neuroinflammation process. With the use of mice expressing a UPS reporter [mice expressing the UPS reporter ubiquitin G76V ‐green fluorescent protein (UbGFP mice)], we found that LPS‐induced acute neuroinflammation status causes a UPS impairment in astrocytes and microglial cells by a mechanism dependent on P2Y 2 R. In this line, LPS‐treated double transgenic UbGFP; P2Y 2 R −/− mice did not present a UPS impairment in astrocytes or a social interaction deficit as severe as that observed in LPS‐treated UbGFP mice. In vivo administration of selective P2Y 2 R agonist diuridine tetraphosphate reversed the UPS impairment completely in astrocytes and partially in microglial cells, promoting increased expression of the proteasomal β5 subunit by a mechanism dependent on the Src/ PI3K/ERK pathway. Altogether, our results suggest that LPS induces unbalanced proteostasis in astrocytes by blocking P2Y 2 R. Finally, our findings point to the design of selective P2Y 2 R agonist drugs as a new therapeutic approach to treat the neuroinflammatory status.—De Diego García, L., Sebastián‐Serrano, Á., Hernández, I. H., Pintor, J., Lucas, J. J., Díaz‐Hernández, M. The regulation of proteostasis in glial cells by nucleotide receptors is key in acute neuroinflammation. FASEB J. 32, 3020–3032 (2018). www.fasebj.org