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.
Phase-change contrast agents (PCCAs) are liquid nanodroplets (ND) that transition into gas microbubbles (MB) when exposed to pulsed ultrasound (US) . The purpose of this study was to investigate the activation threshold of size-isolated PCCAs under physiologically relevant hydrostatic pressures. Size-isolated PFB NDs were prepared using an extrusion method and filter sizes of 100 or 400 nm. Using a programmable US scanner and linear array transducer, a custom scan sequence was implemented that interleaved pulsed US transmissions for both PCCA activation and MB detection. An automated US pressure sweep was performed (3 to 6 MPa, N = 200 discrete intervals), and grayscale US images were acquired at each increment. PCCAs were circulated through a flow phantom at 37 deg. Hydrostatic pressures applied to the PCCAs was controlled by constriction of flow phantom tubing. Reference measures were recorded by a calibrated pressure catheter. Activation thresholds were quantified using custom MATLAB software. The US-detected PCCA activation threshold increased with increased hydrostatic pressure in the range of 0 to 75 mmHg. The 100 nm size-isolated PCCAs activated at a higher US pressure as compared to 400 nm agents (4.3 ± 0.2 mmHg versus 3.7 ± 0.2 mmHg, p < 0.001). A positive correlation was found between the PCCA activation threshold and applied hydrostatic pressure for both 100 and 400 nm PCCAs (R 2 > 0.95, p < 0.001). This strong linear relationship could be exploited for noninvasive pressure estimation using US and PCCAs.
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