Charité Center 12 (CC12) for Internal Medicine and Dermatology, Department of Psychosomatics, Psychoneuroimmunology of the Skin, Charité-University Medicine Berlin, Berlin, Germany.
J Invest Dermatol. 2011 Mar;131(3):735-43. doi: 10.1038/jid.2010.317. Epub 2010 Nov 18.
Neuroimmune dysregulation characterizes atopic disease, but its nature and clinical impact remain ill-defined. Induced by stress, the neurotrophin nerve growth factor (NGF) may worsen cutaneous inflammation. We therefore studied the role of NGF in the cutaneous stress response in a mouse model for atopic dermatitis-like allergic dermatitis (AlD). Combining several methods, we found that stress increased cutaneous but not serum or hypothalamic NGF in telogen mice. Microarray analysis showed increased mRNAs of inflammatory and growth factors associated with NGF in the skin. In stress-worsened AlD, NGF-neutralizing antibodies markedly reduced epidermal thickening together with NGF, neurotrophin receptor (tyrosine kinase A and p75 neurotrophin receptor), and transforming growth factor-β expression by keratinocytes but did not alter transepidermal water loss. Moreover, NGF expression by mast cells was reduced; this corresponded to reduced cutaneous tumor necrosis factor-α (TNF-α) mRNA levels but not to changes in mast cell degranulation or in the T helper type 1 (Th1)/Th2 cytokine balance. Also, eosinophils expressed TNF receptor type 2, and we observed reduced eosinophil infiltration after treatment with NGF-neutralizing antibodies. We thus conclude that NGF acts as a local stress mediator in perceived stress and allergy and that increased NGF message contributes to worsening of cutaneous inflammation mainly by enhancing epidermal hyperplasia, pro-allergic cytokine induction, and allergy-characteristic cellular infiltration.
神经免疫失调是特应性疾病的特征，但它的性质和临床影响仍不清楚。神经生长因子（NGF）是一种由应激诱导的神经营养因子，可能会加重皮肤炎症。因此，我们在特应性皮炎样过敏性皮炎（AlD）的小鼠模型中研究了 NGF 在皮肤应激反应中的作用。通过结合几种方法，我们发现应激增加了休止期小鼠的皮肤而非血清或下丘脑 NGF。微阵列分析显示，皮肤中与 NGF 相关的炎症和生长因子的 mRNA 表达增加。在应激加重的 AlD 中，NGF 中和抗体显著减少表皮增厚，同时减少角质形成细胞中 NGF、神经营养因子受体（酪氨酸激酶 A 和 p75 神经营养因子受体）和转化生长因子-β的表达，但不改变经皮水分丢失。此外，肥大细胞的 NGF 表达减少；这与皮肤肿瘤坏死因子-α（TNF-α）mRNA 水平降低相对应，但与肥大细胞脱颗粒或辅助性 T 细胞 1（Th1）/Th2 细胞因子平衡的变化无关。此外，嗜酸性粒细胞表达 TNF 受体 2，并且我们观察到在用 NGF 中和抗体治疗后，嗜酸性粒细胞浸润减少。因此，我们得出结论，NGF 作为一种局部应激介质在感知应激和过敏中起作用，并且增加的 NGF 信号通过增强表皮过度增生、诱导促过敏细胞因子和过敏特征性细胞浸润来加重皮肤炎症。
