Intercellular Arc Signaling Regulates Vasodilation

Abstract

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.

A cryo-ET survey of microtubules and intracellular compartments in mammalian axons

“…Instead of viral contamination, these nonmembranous compartments may be examples of endogenous capsid assemblies such as Arc. These transfer mRNA between neurons ( Ashley et al, 2018 ; Pastuzyn et al, 2018 ), are key regulators of synaptic plasticity ( Plath et al, 2006 ), and regulate inflammation in DRG neurons ( de la Peña et al, 2021 ). However, purified recombinant rat Arc capsids are 32 nm in diameter ( Pastuzyn et al, 2018 ), and Dm Arc capsids have a diameter of 37 nm ( Erlendsson et al, 2020 ), which are both larger than the 27-nm-wide particles we observe.…”

Astragaloside IV ameliorates radiation‐induced nerve cell damage by activating the BDNF/TrkB signaling pathway

“…Then, compared with the Control and DMSO groups, Ras , Creb , and C‐fos that related cell proliferation, differentiation, and growth (Abankwa & Gorfe, 2020; Shankar et al, 2016; Tregnago et al, 2016) were significantly decreased in radiation group ( p < 0.001, p < 0.05, and p < 0.001), while 40 mg/kg AS‐IV increased significantly ( p < 0.01, p < 0.05, and p < 0.05). Additionally, we tested Gap‐43 , Psd‐95 , and Arc levels that were related to neuronal development and plasticity (Benowitz & Routtenberg, 1997; de la Peña et al, 2021; LaBate & Skene, 1989; Vallejo et al, 2017). The levels of Gap‐43 , Psd‐95 , and Arc in irradiated mice were significantly decreased compared with normal mice ( p < 0.001, p < 0.01, and p < 0.01).…”

A compendium of validated pain genes

“…Taken together, these results point to future avenues of osteoarthritic pharmaceutical development that could jointly address pain management and joint morphology through combined targeting of NGF, MMP13, and IL‐1B. In addition to these genetic models, local injection of NGF has been used as a key inflammatory mediator in behavioral models given that NGF serves as a potentiator of protein synthesis (Barragan‐Iglesias et al, 2021 ; Melemedjian et al, 2010 ; de la Peña, Barragan‐Iglesias, et al, 2021 ; de la Peña, Kunder, et al, 2021 ).…”

“…This includes genome‐wide measurements of mRNA levels in tissues and individual cells (K. D. Jones et al, 2016 ; Kupari et al, 2021 ; Ray et al, 2018 ; Usoskin et al, 2014 ; Uttam et al, 2018 ). Given the discordance between mRNA levels and translational output, there is growing interest in the use of methods that analyze translational efficiency as a means of precisely quantifying protein synthesis rates in response to painful stimuli (Barragan‐Iglesias et al, 2021 ; Megat, Ray, Moy, et al, 2019 ; Megat, Ray, Tavares‐Ferreira, et al, 2019 ; de la Peña, Barragan‐Iglesias, et al, 2021 ). Gene disruption provides an essential means of testing hypotheses that result from these powerful reverse genetic approaches.…”