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The impact of inflammatory mediators on the landscape of nascent translation in the dorsal root ganglion.

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      Translational regulation of mRNA permeates nociception. The identities of transcripts subject to translational control are almost entirely unknown. To address this problem, we examine the landscape of nascent translation in DRG neurons treated with inflammatory mediators using ribosome profiling. We identify and validate two targets, the immediate early genes Arc and Fos, as targets of induced translation. Mechanistically, we demonstrate that the ribosomal protein S6 kinase (S6K1) is required for their biosynthesis. Pharmacologic blockade of either S6K1 or Fos attenuates mechanical and thermal hyperalgesia triggered by inflammatory stimuli. Genetic disruption of Arc did not alter pain associated behaviors. However, Arc deficient mice display exaggerated paw temperatures and vasodilation in response to an inflammatory challenge. Since Arc has recently been shown to be released from neurons in extracellular vesicles, we asked if intercellular Arc signaling regulates the inflammatory response in skin. We found that the excessive thermal responses and vasodilation observed in Arc defective mice are rescued by injection of Arc-containing extracellular vesicles into the skin. Collectively, our results suggest that activity-dependent translation in the DRG supports at least two critical functions: neurogenic inflammation (via Arc) and nociception (via Fos).
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