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This study examined peripheral nerve injury increases levels of interleukin-1β (IL-1β), which contributes to nociceptive hypersensitivity. IL-1β is matured by inflammasomes; e.g., absent in melanoma 2 (AIM2) and NLR family pyrin domain containing 3 (NLRP3), which are activated by a variety of signals like reactive oxygen species (ROS). Inflammasomes also mature gasdermin D which creates pores in the cell membrane, allowing for release of IL-1β. However, it is not fully known which inflammasomes are activated after peripheral nerve injury, where they are activated, and whether GSDMD-dependent pores form to allow IL-1β release. In addition to addressing these questions, we further tested whether scavenging ROS by pharmacological activation of NRF2 would attenuate activation of inflammasomes. Male and female C57BL/6J mice underwent sciatic nerve chronic constriction injury (CCI). Sciatic nerve (SN), dorsal root ganglion (DRG), and spinal cord were harvested after 0, 1, 5, 7, 14, and 21 days after injury to measure transcription of inflammasome components. Propidium iodide was administered by i.p. injection one hour before taking tissue to measure pore formation. NRF2 was pharmacologically activated by CPUY192018 (30 mg/kg daily for three days; i.p.). Mechanical allodynia was quantified by von Frey tests. There was an early increase in gene expression of inflammasome components after injury, with a preference towards NLRP3 in male mice and AIM2 in female mice. This trend was repeated at days 14 and 21. A high expression of caspase 1 and interleukin 1 beta (IL-1B) was observed throughout the SN and DRG, but propidium iodide staining indicated pyroptosis only occurred in the injured SN. Effects of CPUY192018 treatment will be presented. Different inflammasomes may be responsible for IL-1β processing and release in males and females. Although inflammasome components are upregulated in DRG, there is little pore formation, suggesting additional regulation of IL-1β release at this site. Grant support from NIH 1RF1NS113840-01.
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