Journal
ALLERGY
Volume 78, Issue 6, Pages 1570-1584Publisher
WILEY
DOI: 10.1111/all.15699
Keywords
chronic itch; gastrin-releasing peptide receptor; IL-1 beta; microglia; NLRP3 inflammasome
Categories
Ask authors/readers for more resources
This study discovers the contribution of spinal astrocytes to chronic itch through sensitization of GRPR(+) neurons. It also reveals the interaction between microglia and GRPR(+) neurons in promoting chronic itch.
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-1 beta-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-1 beta production in spinal microglia under chronic itch conditions. Blockade of microglial activation and the NLRP3/caspase-1/IL-1 beta 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-1 beta(+) microglia are localized in close proximity to GRPR(+) neurons. Consistently, intrathecal injection of IL1R1 antagonist or exogenous IL-1 beta indicate that the IL-1 beta-IL-1R1 signaling pathway enhanced the activation of GRPR(+) neurons. Furthermore, our results demonstrate that the microglial NLRP3/caspase-1/IL-1 beta 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-1 beta/IL1R1 axis. These results will provide new insights into the pathophysiology of pruritus and novel therapeutic strategies for patients with chronic itch.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available