Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway

Shih Heng Chen; Yueh Feng Sung; Esteban A. Oyarzabal; Yu Mei Tan; Jeremy Leonard; Mingri Guo; Shuo Li; Qingshan Wang; Chun Hsien Chu; Shiou Lan Chen; Ru Band Lu; Jau Shyong Hong

doi:10.1007/s12035-018-0965-4

Physiological Concentration of Prostaglandin E₂ Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway

Shih Heng Chen, Yueh Feng Sung, Esteban A. Oyarzabal, Yu Mei Tan, Jeremy Leonard, Mingri Guo, Shuo Li, Qingshan Wang, Chun Hsien Chu, Shiou Lan Chen, Ru Band Lu, Jau Shyong Hong

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Abstract

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, gp91^phox, 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.

Original language	English
Pages (from-to)	8001-8013
Number of pages	13
Journal	Molecular Neurobiology
Volume	55
Issue number	10
DOIs	https://doi.org/10.1007/s12035-018-0965-4
Publication status	Published - 2018 Oct 1

All Science Journal Classification (ASJC) codes

Neurology
Cellular and Molecular Neuroscience

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Chen, S. H., Sung, Y. F., Oyarzabal, E. A., Tan, Y. M., Leonard, J., Guo, M., Li, S., Wang, Q., Chu, C. H., Chen, S. L., Lu, R. B., & Hong, J. S. (2018). Physiological Concentration of Prostaglandin E₂ Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway. Molecular Neurobiology, 55(10), 8001-8013. https://doi.org/10.1007/s12035-018-0965-4

@article{dd04e05654854113a1762fe7643b350d,

title = "Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway",

abstract = "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.",

author = "Chen, {Shih Heng} and Sung, {Yueh Feng} and Oyarzabal, {Esteban A.} and Tan, {Yu Mei} and Jeremy Leonard and Mingri Guo and Shuo Li and Qingshan Wang and Chu, {Chun Hsien} and Chen, {Shiou Lan} and Lu, {Ru Band} and Hong, {Jau Shyong}",

note = "Funding Information: This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank Drs. Jerry Liu, Hong Li, Peter Egeghy, and David Herr for the critical reading of the manuscript. We thank the animal care team members, Anthony Lockhart, Katrina Loper, and Johnny Green and the members of Fluorescence Microscopy and Imaging Center, Charles J. Tucker and Agnes Janoshazi. The US Environmental Protection Agency has provided administrative review and has approved this paper for publication. The views expressed in this paper are those of the authors and do not necessarily reflect the views of the US Environmental Protection Agency. Publisher Copyright: {\textcopyright} 2018, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2018",

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doi = "10.1007/s12035-018-0965-4",

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Chen, SH, Sung, YF, Oyarzabal, EA, Tan, YM, Leonard, J, Guo, M, Li, S, Wang, Q, Chu, CH, Chen, SL, Lu, RB & Hong, JS 2018, 'Physiological Concentration of Prostaglandin E₂ Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway', Molecular Neurobiology, vol. 55, no. 10, pp. 8001-8013. https://doi.org/10.1007/s12035-018-0965-4

TY - JOUR

T1 - Physiological Concentration of Prostaglandin E2 Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway

AU - Chen, Shih Heng

AU - Sung, Yueh Feng

AU - Oyarzabal, Esteban A.

AU - Tan, Yu Mei

AU - Leonard, Jeremy

AU - Guo, Mingri

AU - Li, Shuo

AU - Wang, Qingshan

AU - Chu, Chun Hsien

AU - Chen, Shiou Lan

AU - Lu, Ru Band

AU - Hong, Jau Shyong

N1 - Funding Information: This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank Drs. Jerry Liu, Hong Li, Peter Egeghy, and David Herr for the critical reading of the manuscript. We thank the animal care team members, Anthony Lockhart, Katrina Loper, and Johnny Green and the members of Fluorescence Microscopy and Imaging Center, Charles J. Tucker and Agnes Janoshazi. The US Environmental Protection Agency has provided administrative review and has approved this paper for publication. The views expressed in this paper are those of the authors and do not necessarily reflect the views of the US Environmental Protection Agency. Publisher Copyright: © 2018, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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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Physiological Concentration of Prostaglandin E₂ Exerts Anti-inflammatory Effects by Inhibiting Microglial Production of Superoxide Through a Novel Pathway

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