Ikehata Yousuke, Oshima Eri, Hayashi Yoshinori, Tanaka Yukinori, Sato Hitoshi, Hitomi Suzuro, Shiratori-Hayashi Miho, Urata Kentaro, Kimura Yuki, Shibuta Ikuko, Ohba Seigo, Iwata Koichi, Mizuta Kentaro, Shirota Tatsuo, Shinoda Masamichi
Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 142-8515, Japan; Department of Physiology, Nihon University School of Dentistry, 1-8-13, Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
Department of Physiology, Nihon University School of Dentistry, 1-8-13, Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
Brain Behav Immun. 2025 Jan;123:982-996. doi: 10.1016/j.bbi.2024.11.003. Epub 2024 Nov 3.
Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in naïve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca concentration and subsequent enhancement of Ca influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain.
三叉神经节（TG）神经元的外周神经损伤通过诱导神经炎症导致顽固性口面部神经性疼痛。然而，这一过程的细节尚未完全明了。在此，我们发现成纤维细胞衍生的白细胞介素（IL）-33是眶下神经损伤（IONI）后触须垫皮肤机械性异常性疼痛发生所必需的。当小鼠出现机械性异常性疼痛时，IONI后TG中IL-33的量增加。TG中IL-33的中和抑制了IONI诱导的机械性异常性疼痛的发生。相反，向TG内注射重组人IL-33（rhIL-33）可在未处理的小鼠中引发机械性异常性疼痛。IL-33及其受体分别在TG中的成纤维细胞和神经元中特异性表达。成纤维细胞消融导致TG中IL-33缺失，并延缓了IONI后机械性异常性疼痛的发生。rhIL-33使原代培养的TG神经元内细胞内钙浓度升高，并随后通过瞬时受体电位锚蛋白1（TRPA1）增强钙内流。此外，rhIL-33促进了TG中TRPA1的膜转位。TG内注射rhIL-33引起的机械性异常性疼痛在药理学阻断或TG中TRPA1基因沉默后显著受到抑制。蛋白激酶A的抑制消除了TRPA1膜转位，并延缓了IONI后的机械性异常性疼痛。P物质刺激导致原代培养的成纤维细胞中IL-33表达上调。在TG中预先给予神经激肽-1受体拮抗剂可减轻IONI后的机械性异常性疼痛和IL-33表达。综上所述，这些结果表明成纤维细胞衍生的IL-33通过抑制致瘤性2（ST2）-TRPA1信号传导加剧TG神经元兴奋性，最终导致口面部神经性疼痛。
