The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China.
Allergy. 2023 Jun;78(6):1570-1584. doi: 10.1111/all.15699. Epub 2023 Mar 13.
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.
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.
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.
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.
脊髓星形胶质细胞通过敏化表达胃泌素释放肽受体 (GRPR) 的瘙痒特异性神经元来促进慢性瘙痒。然而，小胶质细胞-神经元相互作用是否有助于瘙痒仍不清楚。在这项研究中，我们旨在探索小胶质细胞如何与 GRPR 神经元相互作用并促进慢性瘙痒。
进行 RNA 测序、定量实时 PCR、western blot、免疫组织化学、RNAscope ISH、药理学和遗传学方法，以研究脊髓 NLRP3（NOD 样受体家族，含 pyrin 结构域 3）炎性小体激活和 IL-1β-IL1R1 信号在慢性瘙痒中的作用。使用 Grpr-eGFP 和 Grpr KO 小鼠来研究小胶质细胞-GRPR 神经元相互作用。
我们观察到慢性瘙痒条件下脊髓小胶质细胞中 NLRP3 炎性小体的激活和 IL-1β 的产生。小胶质细胞激活和 NLRP3/caspase-1/IL-1β 轴的阻断减轻了慢性瘙痒和神经元激活。GRPR 神经元表达 1 型白细胞介素 1 受体 (IL-1R1)，这对于慢性瘙痒的发展至关重要。我们的研究还发现，IL-1β 小胶质细胞定位于 GRPR 神经元附近。同样，鞘内注射 IL1R1 拮抗剂或外源性 IL-1β 表明，IL-1β-IL-1R1 信号通路增强了 GRPR 神经元的激活。此外，我们的结果表明，小胶质细胞 NLRP3/caspase-1/IL-1β 轴有助于由小分子和环境中的蛋白质过敏原以及药物引发的几种不同的慢性瘙痒。
我们的研究结果揭示了一种未知的机制，即小胶质细胞通过 NLRP3/caspase-1/IL-1β/IL1R1 轴增强 GRPR 神经元的激活。这些结果将为瘙痒的病理生理学提供新的见解，并为慢性瘙痒患者提供新的治疗策略。
