Lv Hao, Wang Yunfei, Tan Lu, Xie Yulie, Liu Peiqiang, Guan Mengting, Cong Jianchao, Xu Yu
Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, Wuhan, China.
Research (Wash D C). 2025 Sep 25;2025:0897. doi: 10.34133/research.0897. eCollection 2025.
The hypersensitive state of the central nervous system, commonly known as central sensitization, presumably drives allergic rhinitis (AR) pathogenesis. However, the involvement of central sensitization in AR and its related mechanisms have rarely been studied. An AR mouse model was induced via ovalbumin treatment. Activation of trigeminal nucleus caudalis (TNC) neurons was assessed by electrophysiological recordings and immunofluorescence staining. The role of TNC neurons in AR was investigated by selectively manipulating them through chemogenetics. The contribution of microglial neuroinflammation to central sensitization and AR was assessed by pharmacologically inhibiting microglial activation. The mechanism of central sensitization in AR was further determined using a microglia-neuron co-culture system. The role of interleukin (IL)-4 in neuroinflammation in AR was explored using in vivo and in vitro methods. The intrinsic neuronal excitability and molecular markers of central sensitization were increased within the TNC of AR mice. Chemogenetic inhibition of TNC neurons ameliorated nasal symptoms, histological changes, autonomic dysfunction, and immune imbalance in AR mice. Moreover, AR mice exhibited an increased number of pro-inflammatory microglia, activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, and enhanced IL-1β production in the TNC. Pharmacological inhibition of microglial activation reduced central sensitization in AR mice and was accompanied by remission of AR. Transcriptomics analysis revealed the inflammatory-prone characteristics of IL-4-treated microglia. IL-4 exposure enhanced lipopolysaccharide-stimulated NLRP3 inflammasome activation in microglia. Intracerebral injection of IL-4 neutralizing antibodies ameliorates neuroinflammation and central sensitization in AR mice and was accompanied by remission of AR. This research uncovers a previously unidentified mechanism wherein microglial neuroinflammation-induced central sensitization in the TNC contributes to AR, providing a new promising approach for the treatment of AR. IL-4 induces noncanonical pro-inflammatory-prone microglia and participates in microglial NLRP3 inflammasome activation in AR.
中枢神经系统的超敏状态，通常称为中枢敏化，可能驱动变应性鼻炎（AR）的发病机制。然而，中枢敏化在AR中的参与情况及其相关机制鲜有研究。通过卵清蛋白处理诱导建立AR小鼠模型。通过电生理记录和免疫荧光染色评估三叉神经尾核（TNC）神经元的激活情况。通过化学遗传学选择性操纵TNC神经元来研究其在AR中的作用。通过药理学抑制小胶质细胞激活来评估小胶质细胞神经炎症对中枢敏化和AR的作用。使用小胶质细胞-神经元共培养系统进一步确定AR中枢敏化的机制。采用体内和体外方法探索白细胞介素（IL）-4在AR神经炎症中的作用。AR小鼠的TNC内固有神经元兴奋性和中枢敏化的分子标志物增加。化学遗传学抑制TNC神经元可改善AR小鼠的鼻部症状、组织学变化、自主神经功能障碍和免疫失衡。此外，AR小鼠的TNC中促炎小胶质细胞数量增加，NOD样受体蛋白3（NLRP3）炎性小体激活，IL-1β产生增强。药理学抑制小胶质细胞激活可降低AR小鼠的中枢敏化，并伴有AR缓解。转录组学分析揭示了IL-4处理的小胶质细胞的炎症易感性特征。IL-4暴露增强了小胶质细胞中脂多糖刺激的NLRP3炎性小体激活。脑内注射IL-4中和抗体可改善AR小鼠的神经炎症和中枢敏化，并伴有AR缓解。本研究揭示了一种先前未被识别的机制，即小胶质细胞神经炎症诱导的TNC中枢敏化促成AR，为AR治疗提供了一种新的有前景的方法。IL-4诱导非经典的炎症易感性小胶质细胞并参与AR中小胶质细胞NLRP3炎性小体激活。
