Background

T_H2 cell–released IL-31 is a critical mediator in patients with atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuroimmune axis of the skin is unknown.

Objective

We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31–induced itch and neuroepidermal communication in patients with AD.

Methods

Ca²⁺ imaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31–stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects.

Results

In human DRGs we confirmed expression and co-occurrence of oncostatin M receptor β subunit and IL-31 receptor A in a small subset of the neuronal population. Furthermore, IL-31 activated approximately 50% of endothelin-1–responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced soluble N-ethylmaleimide–sensitive factor activating protein receptor–dependent BNP release. In Grhl3PAR2^/+ mice house dust mite–induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31 transgenic mice also exhibited increased Nppb transcripts in DRGs and the skin; accordingly, skin BNP receptor levels were increased. Importantly, expression of BNP and its receptor were increased in the skin of patients with AD. In human skin cells BNP stimulated a proinflammatory and itch-promoting phenotype.

Conclusion

For the first time, our findings show that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and the skin. IL-31 enhances BNP release and synthesis and orchestrates cytokine and chemokine release from skin cells, thereby coordinating the signaling pathways involved in itch. Inhibiting peripheral BNP function might be a novel therapeutic strategy for AD and pruritic conditions.

中文翻译：

---

IL-31引起的特应性皮炎的新机制

背景

T _H 2细胞释放的IL-31是特应性皮炎（AD）患者的关键介质，特应性皮炎是一种普遍且使人衰弱的慢性皮肤疾病。脑源性利钠肽（BNP）已被描述为中枢瘙痒介质。BNP在周围（皮肤衍生的）瘙痒中的重要性及其在皮肤神经免疫轴内与IL-31的功能联系尚不明确。

客观的

我们试图研究BNP在AD患者IL-31引起的瘙痒和神经表皮通讯中在外周感觉系统和皮肤中的作用。

方法

进行了Ca ²⁺成像，免疫组织化学，定量实时PCR，RNA测序，敲低，细胞因子/磷酸激酶阵列，酶免疫测定和药理抑制作用，以检查IL-31刺激的BNP相关的瘙痒信号传导的细胞基础。 AD和健康受试者的背根神经节神经元（DRG）和皮肤细胞，转基因AD样小鼠模型以及人皮肤中的表达。

结果

在人DRG中，我们证实了在神经元群体的一小部分中抑癌素M受体β亚基和IL-31受体A的表达和共存。此外，IL-31激活了约50％的内皮素1反应神经元，后者的一半也对组胺反应。在鼠类DRG中，IL-31上调了Nppb，并诱导了可溶性N-乙基马来酰亚胺敏感因子激活蛋白受体依赖性BNP的释放。在Grhl3PAR2 ^{/ +}小鼠中，尘螨诱导的严重AD样皮炎与Nppb上调相关。受损的IL-31转基因小鼠也表现出Nppb升高DRG和皮肤中的转录本；因此，皮肤BNP受体水平升高。重要的是，AD患者皮肤中BNP及其受体的表达增加。在人的皮肤细胞中，BNP刺激了促炎和促进瘙痒的表型。

结论

我们的发现首次表明BNP与AD有关，IL-31调节DRG和皮肤中的BNP。IL-31增强BNP的释放和合成，并协调皮肤细胞中细胞因子和趋化因子的释放，从而协调痒相关的信号传导途径。抑制外周血BNP功能可能是AD和瘙痒病的一种新型治疗策略。