Zhang Zehua, Yan Xiaohan, Kang Le, Leng Zhuyun, Ji Yingjie, Yang Shuangzhu, Du Xiaojing, Fang Kang, Wang Zeyu, Li Zhaoxing, Sun Mingchuang, Zhao Ziying, Feng Anqi, Chen Zhukai, Zhang Shihan, Wan Dong, Chen Tao, Xu Meidong
Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.
Cell Death Dis. 2024 Jan 27;15(1):91. doi: 10.1038/s41419-024-06480-5.
Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3β from the Wnt/β-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven β-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3β, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.
瞬时受体电位香草酸亚家族成员8（TRPM8）是初级感觉神经元中的一种冷觉感受器，可调节多种神经元功能。P物质（SP）是神经元分泌的一种促炎神经肽，会加重结肠炎。然而，TRPM8在SP释放中的调节作用仍不清楚。我们的研究旨在探讨TRPM8在结肠炎期间初级感觉神经元释放SP中的作用，并阐明SP对结肠上皮的影响。我们分析了来自基因表达综合数据库中炎症性肠病患者的数据。本实验使用葡聚糖硫酸钠（DSS，2.5%）诱导的小鼠结肠炎、小鼠背根神经节（DRG）神经元、ND7/23细胞系以及小鼠或人类结肠类器官。我们的研究发现，TRPM8、TAC1和WNT3A的表达与患者溃疡性结肠炎的严重程度以及DSS诱导的小鼠结肠炎的严重程度显著相关。TRPM8激动剂（薄荷醇）和SP受体拮抗剂（阿瑞匹坦）可减轻小鼠结肠炎，但二者作用无叠加效应。薄荷醇促进小鼠DRG神经元中的钙离子内流，并抑制cAMP信号通路中的PKAca以及Wnt/β-连环蛋白信号通路中的GSK-3β的结合和磷酸化，从而抑制Wnt3a驱动的β-连环蛋白对促进ND7/23细胞中SP释放的作用。长期用SP刺激会抑制小鼠和人类结肠类器官的增殖并增强其凋亡。总之，TRPM8通过抑制PKAca与GSK-3β之间的相互作用来抑制初级感觉神经元释放SP，从而抑制SP促进结肠上皮细胞凋亡的作用并缓解结肠炎。
