Injury responses require communication between different cell types in the skin. Sensory neurons contribute to inflammation and can secrete signaling molecules that affect non-neuronal cells. Despite the pervasive role of translational regulation in nociception, the contribution of activity-dependent protein synthesis to inflammation is not well understood. To address this problem, we examined the landscape of nascent translation in murine dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We identified the activity-dependent gene, Arc, as a target of translation in vitro and in vivo. Inflammatory cues promote local translation of Arc in the skin. Arc-deficient male 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 (EVs), we hypothesized that 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 EVs into the skin. Our findings suggest that activity-dependent production of Arc in afferent fibers regulates neurogenic inflammation potentially through intercellular signaling.

SIGNIFICANCE STATEMENT Nociceptors play prominent roles in pain and inflammation. We examined rapid changes in the landscape of nascent translation in cultured dorsal root ganglia (DRGs) treated with a combination of inflammatory mediators using ribosome profiling. We identified several hundred transcripts subject to rapid preferential translation. Among them is the immediate early gene (IEG) Arc. We provide evidence that Arc is translated in afferent fibers in the skin. Arc-deficient mice display several signs of exaggerated inflammation which is normalized on injection of Arc containing extracellular vesicles (EVs). Our work suggests that noxious cues can trigger Arc production by nociceptors which in turn constrains neurogenic inflammation in the skin.

损伤反应需要皮肤中不同细胞类型之间的交流。感觉神经元有助于炎症，并可以分泌影响非神经元细胞的信号分子。尽管翻译调节在伤害感受中具有普遍作用，但活性依赖性蛋白质合成对炎症的贡献尚不清楚。为了解决这个问题，我们使用核糖体分析检查了用炎症介质处理的小鼠背根神经节 (DRG) 神经元的新生翻译情况。我们确定了活性依赖性基因 Arc 作为体外和体内翻译的目标. 炎症提示促进皮肤中 Arc 的局部翻译。电弧缺陷的雄性小鼠表现出夸大的爪子温度和血管舒张，以应对炎症挑战。由于最近已证明 Arc 可从细胞外囊泡 (EV) 中的神经元中释放出来，因此我们假设细胞间 Arc 信号传导调节皮肤的炎症反应。我们发现，在 Arc 缺陷小鼠中观察到的过度热反应和血管舒张可以通过将含有 Arc 的 EV 注射到皮肤中来挽救。我们的研究结果表明，传入纤维中 Arc 的活动依赖性产生可能通过细胞间信号传导调节神经源性炎症。

意义声明伤害感受器在疼痛和炎症中发挥重要作用。我们使用核糖体分析检查了用炎症介质组合处理的培养的背根神经节 (DRG) 中新生翻译景观的快速变化。我们确定了数百个需要快速优先翻译的转录本。其中包括直接早期基因 (IEG) Arc。我们提供的证据表明 Arc 在皮肤的传入纤维中被翻译。Arc 缺陷小鼠表现出几种过度炎症的迹象，这些迹象在注射含有 Arc 的细胞外囊泡 (EV) 时会正常化。我们的工作表明，有害线索可以触发伤害感受器产生电弧，进而抑制皮肤的神经源性炎症。