Inflammatory activation of astroglia adds to the pathology of various neurological\ndiseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1alpha (IL-1alpha)\nwith enhanced inflammatory signaling.This provokes pro-inflammatory gene expression\nof, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2\n(Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely\nstudied, pathways related to how metabolism modulates inflammatory signaling in astrocytes\nare underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects\ninflammatory responses towards IL-1alpha and tumor necrosis factor alpha in neonatal rat astrocytes.\nBlocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect\nactivation of inflammatory signaling by IL-1alpha, but did elicit differential effects on inflammatory gene\nmRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1alpha was consistently\nup-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted\nfrom mRNA stabilization. Mitochondrial inhibitors also increased IL-1alpha-triggered secretion of\neicosanoids, such as prostaglandin E2, prostaglandin F2alpha, and 6-keto-prostaglandin F1alpha, as assessed\nby liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation\nelevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK).\nAMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators\nrecapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte\ninflammatory responses by oxidative metabolism, with relevance towards eicosanoid production.
Loading....