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Open AccessArticle

Inhibitors of Oxidative Phosphorylation Modulate Astrocyte Inflammatory Responses through AMPK-Dependent Ptgs2 mRNA Stabilization

1
Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia
2
Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
3
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, 60596 Frankfurt, Germany
4
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
*
Author to whom correspondence should be addressed.
Cells 2019, 8(10), 1185; https://doi.org/10.3390/cells8101185
Received: 10 September 2019 / Revised: 30 September 2019 / Accepted: 1 October 2019 / Published: 1 October 2019
(This article belongs to the Special Issue Study around Neuroinflammation)
Inflammatory activation of astroglia adds to the pathology of various neurological diseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1α (IL-1α) with enhanced inflammatory signaling. This provokes pro-inflammatory gene expression of, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2 (Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely studied, pathways related to how metabolism modulates inflammatory signaling in astrocytes are underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects inflammatory responses towards IL-1α and tumor necrosis factor α in neonatal rat astrocytes. Blocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect activation of inflammatory signaling by IL-1α, but did elicit differential effects on inflammatory gene mRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1α was consistently up-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted from mRNA stabilization. Mitochondrial inhibitors also increased IL-1α-triggered secretion of eicosanoids, such as prostaglandin E2, prostaglandin F, and 6-keto-prostaglandin F, as assessed by liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation elevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK). AMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators recapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte inflammatory responses by oxidative metabolism, with relevance towards eicosanoid production. View Full-Text
Keywords: astrocytes; inflammation; mitochondria; prostaglandins astrocytes; inflammation; mitochondria; prostaglandins
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Astakhova, A.; Chistyakov, D.; Thomas, D.; Geisslinger, G.; Brüne, B.; Sergeeva, M.; Namgaladze, D. Inhibitors of Oxidative Phosphorylation Modulate Astrocyte Inflammatory Responses through AMPK-Dependent Ptgs2 mRNA Stabilization. Cells 2019, 8, 1185.

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