Psychoneuroimmunology Laboratory, Department of Psychosomatic Medicine and Psychotherapy, Justus Liebig University Giessen, 35390 Giessen, Germany.
Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany.
Int J Mol Sci. 2024 May 24;25(11):5738. doi: 10.3390/ijms25115738.
Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.
应激暴露会大大加重过敏炎症性疾病。肥大细胞 (MCs) 在周围免疫对神经内分泌应激介质（如神经生长因子 (NGF) 和 P 物质 (SP)）的反应中发挥关键作用。肥大细胞蛋白酶 (MCPs) 和胆碱能因子 (Chrna7、SLURP1) 最近被描述为调节 MC 应激反应。我们在噪声诱导应激 (NiS) 和特应性皮炎样过敏炎症 (AlD) 的小鼠模型以及缺乏 Chrna7 的培养 MC 中研究了 MCPs 和 Chrna7/SLURP1 及其相互作用。我们发现，胆碱能应激轴与 AlD 中的神经内分泌应激介质和应激介导的切割酶相互作用。SP 切割 mMCP4+MC 在 AlD 中上调，在 NiS+AlD 中进一步上调。抗 NGF 中和抗体治疗阻断了体内的应激诱导上调，并且 mMCP4+MC 与 AlD 疾病活动的测量相关。最后，对 SP 的高 mMCP4 产生取决于培养 MC 中的 Chrna7/SLURP1。总之，mTCP4 及其由 Chrna7/SLURP1 上调的上游调控是治疗过敏炎症及其由应激加重的有趣新靶点。
