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Inhibitors of Oxidative Phosphorylation Modulate Astrocyte Inflammatory Responses through AMPK-Dependent Ptgs2 mRNA
Alina Astakhova1, Dmitry Chistyakov2, Dominique Thomas3
1Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia. alina_astakhova@yahoo.com.
Abstract:
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 F2α, and 6-keto-prostaglandin F1α, 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.
Insights
Mitochondrial dysfunction in astrocytes amplifies inflammatory responses, increasing prostaglandin endoperoxide synthase 2 (Ptgs2) expression and eicosanoid production. This occurs via AMP-activated protein kinase (AMPK) activation, highlighting metabolic control of neuroinflammation.
Area of Science:
- Neuroscience
- Cellular Metabolism
- Immunology
Background:
- Astrocyte inflammatory activation contributes to neurological disease pathology.
- Astrocytes respond to cytokines like interleukin-1α (IL-1α) with inflammatory signaling, upregulating genes such as prostaglandin endoperoxide synthase 2 (Ptgs2).
- Metabolic regulation of astrocyte inflammatory signaling is poorly understood compared to innate immune cells.
Purpose of the Study:
- To investigate how mitochondrial oxidative phosphorylation impacts inflammatory responses in neonatal rat astrocytes.
- To determine the role of mitochondrial metabolism in astrocyte signaling pathways activated by IL-1α and tumor necrosis factor α.
Main Methods:
- Neonatal rat astrocytes were treated with mitochondrial inhibitors targeting respiratory complexes and ATP synthase.
- Inflammatory gene expression (Ptgs2) and eicosanoid secretion were analyzed.
- Mechanisms involving adenosine monophosphate (AMP) and AMP-activated protein kinase (AMPK) were investigated.
Main Results:
- Inhibition of oxidative phosphorylation did not affect IL-1α signaling activation but altered inflammatory gene expression.
- Ptgs2 mRNA and protein expression were consistently upregulated by IL-1α upon oxidative phosphorylation inhibition, due to mRNA stabilization.
- Mitochondrial inhibitors increased IL-1α-triggered secretion of prostaglandins (PGE2, PGF2α, 6-keto-PGF1α).
- Reduced oxidative phosphorylation elevated AMP levels and activated AMPK, which was essential for Ptgs2 upregulation.
Conclusions:
- Oxidative metabolism modulates astrocyte inflammatory responses, specifically influencing eicosanoid production.
- AMPK activation mediates the effect of mitochondrial dysfunction on Ptgs2 mRNA stability and inflammatory gene expression in astrocytes.
- These findings reveal a critical link between astrocyte metabolism and neuroinflammation, with implications for neurological diseases.
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