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Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway
Citation:
Chen, S., Y. Sung, E. Oyarzabal, C. Tan, J. Leonard, M. Guo, S. Li, Q. Wang, C. Chu, S. Chen, R. Lu, AND J. Hong. Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway. Molecular Neurobiology. Springer, Heidelburg, Germany, 55(10):8001-8013, (2018). https://doi.org/10.1007/s12035-018-0965-4
Impact/Purpose:
Prostaglandin E2 (PGE2), a small lipid mediator, has long been associated with inflammatory conditions in both the peripheral and central nervous system (CNS). Previous reports demonstrated that PGE2 elicited its functions via binding with four distinct G protein-coupled receptors (GPCR), designated EP1, EP2, EP3, and EP4. However, an important consideration is that majority of studies use PGE2 concentrations occurred in pathological conditions ranging from 100 nM to 10 μM, which are 100- to 1000-fold higher than physiological concentrations of PGE2 in the CNS (< 10 nM). In this study we investigate whether PGE2 still possesses immune regulatory function under normal physiological condition. The results showed that physiological concentration of PGE2 could protect dopaminergic neurons against LPS-induced neurotoxicity through a reduction of microglial release of pro-inflammatory factors through an EP receptor-independent novel action mechanism. The neuroprotective effects elicited by PGE2 were mediated by the inhibition of microglial NOX2, a major superoxide-producing enzyme. This is the first report that PGE2 could directly inhibit the catalytic subunit of NOX2 (gp91phox) to suppress microglia activation. Most importantly, this study revealed a potential physiological role of PGE2 in maintaining brain immune homeostasis and protecting neurons via an EP receptor-independent mechanism.
Description:
This study investigated the physiological regulation of brain immune homeostasis in rat primary neuron-glial cultures by sub-nanomolar concentrations of prostaglandin E2 (PGE2). We demonstrated that 0.01 to 10 nM PGE2 protected dopaminergic neurons against LPS-induced neurotoxicity through a reduction of microglial release of pro-inflammatory factors in a dose-dependent manner. Mechanistically, neuroprotective effects elicited by PGE2 were mediated by the inhibition of microglial NOX2, a major superoxide-producing enzyme. This conclusion was supported by (1) the close relationship between inhibition of superoxide and PGE2-induced neuroprotective effects; (2) the mediation of PGE2-induced reduction of superoxide and neuroprotection via direct inhibition of the catalytic subunit of NOX2, gp91phox, rather than through the inhibition of conventional prostaglandin E2 receptors; and (3) abolishment of the neuroprotective effect of PGE2 in NOX2-deficient cultures. In summary, this study revealed a potential physiological role of PGE2 in maintaining brain immune homeostasis and protecting neurons via an EP receptor-independent mechanism.
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DOI: Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway