Microglia–neuron interactions promote chronic itch via the NLRP3‐IL‐1β‐GRPR axis

Abstract Background Spinal astrocytes contribute to chronic itch via sensitization of itch‐specific neurons expressing gastrin‐releasing peptide receptor (GRPR). However, whether microglia–neuron interactions contribute to itch remains unclear. In this study, we aimed to explore how microglia interact with GRPR + neurons and promote chronic itch. Methods RNA sequencing, quantitative real‐time PCR, western blot, immunohistochemistry, RNAscope ISH, pharmacologic and genetic approaches were performed to examine the roles of spinal NLRP3 (The NOD‐like receptor family, pyrin‐containing domain 3) inflammasome activation and IL‐1β‐IL1R1 signaling in chronic itch. Grpr‐eGFP and Grpr KO mice were used to investigate microglia–GRPR + neuron interactions. Results We observed NLRP3 inflammasome activation and IL‐1β production in spinal microglia under chronic itch conditions. Blockade of microglial activation and the NLRP3/caspase‐1/IL‐1β axis attenuated chronic itch and neuronal activation. Type 1 IL‐1 receptor (IL‐1R1) was expressed in GRPR + neurons, which are essential for the development of chronic itch. Our studies also find that IL‐1β + microglia are localized in close proximity to GRPR + neurons. Consistently, intrathecal injection of IL1R1 antagonist or exogenous IL‐1β indicate that the IL‐1β‐IL‐1R1 signaling pathway enhanced the activation of GRPR + neurons. Furthermore, our results demonstrate that the microglial NLRP3/caspase‐1/IL‐1β axis contributes to several different chronic itches triggered by small molecules and protein allergens from the environment and drugs. Conclusion Our findings reveal a previously unknown mechanism in which microglia enhances the activation of GRPR + neurons through the NLRP3/caspase‐1/IL‐1β/IL1R1 axis. These results will provide new insights into the pathophysiology of pruritus and novel therapeutic strategies for patients with chronic itch.