William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, Australia.
Br J Pharmacol. 2022 Apr;179(7):1450-1469. doi: 10.1111/bph.15726. Epub 2022 Feb 14.
Transient receptor potential cation channel subfamily V member 1 (TRPV1) is localized to sensory C-fibres and its opening leads to membrane depolarization, resulting in neuropeptide release and neurogenic inflammation. However, the identity of the endogenous activator of TRPV1 in this setting is unknown. The arachidonic acid metabolites 12-hydroperoxyeicosatetraenoyl acid (12-HpETE) and 20-hydroxyeicosatetraenoic acid (20-HETE) have emerged as potential endogenous activators of TRPV1. However, whether these lipids underlie TRPV1-mediated neurogenic inflammation remains unknown.
We analysed human cantharidin-induced blister samples and inflammatory responses in TRPV1 transgenic mice.
In a human cantharidin-blister model, the potent TRPV1 activators 20-HETE but not 12-HETE (stable metabolite of 12-HpETE) correlated with arachidonic acid levels. Similarly, in mice, levels of 20-HETE (but not 12-HETE) and arachidonic acid were strongly positively correlated within the inflammatory milieu. Furthermore, LPS-induced oedema formation and neutrophil recruitment were substantially and significantly attenuated by pharmacological block or genetic deletion of TRPV1 channels, inhibition of 20-HETE formation or SP receptor neurokinin 1 (NK ) blockade. LPS treatment also increased cytochrome P450 ω-hydroxylase gene expression, the enzyme responsible for 20-HETE production.
Taken together, our findings suggest that endogenously generated 20-HETE activates TRPV1 causing C-fibre activation and consequent oedema formation. These findings identify a novel pathway that may be useful in the therapeutics of diseases/conditions characterized by a prominent neurogenic inflammation, as in several skin diseases.
瞬时受体电位阳离子通道亚家族 V 成员 1（TRPV1）定位于感觉 C 纤维，其开放导致膜去极化，导致神经肽释放和神经源性炎症。然而，这种情况下 TRPV1 的内源性激活剂的身份尚不清楚。花生四烯酸代谢物 12-过氧二十碳四烯酸（12-HpETE）和 20-羟二十碳四烯酸（20-HETE）已成为潜在的 TRPV1 内源性激活剂。然而，这些脂质是否是 TRPV1 介导的神经源性炎症的基础尚不清楚。
我们分析了人类斑蝥素诱导的水疱样本和 TRPV1 转基因小鼠的炎症反应。
在人类斑蝥素水疱模型中，强效 TRPV1 激活剂 20-HETE 而不是 12-HETE（12-HpETE 的稳定代谢物）与花生四烯酸水平相关。同样，在小鼠中，炎症环境中 20-HETE（而非 12-HETE）和花生四烯酸的水平呈强烈的正相关。此外，TRPV1 通道的药理学阻断或基因缺失、20-HETE 形成的抑制或 SP 受体神经激肽 1（NK1）阻断显著减轻了 LPS 诱导的水肿形成和中性粒细胞募集。LPS 处理还增加了细胞色素 P450 ω-羟化酶基因表达，该酶负责 20-HETE 的产生。
综上所述，我们的发现表明，内源性生成的 20-HETE 激活 TRPV1，导致 C 纤维激活，继而导致水肿形成。这些发现确定了一种新的途径，该途径可能对以几种皮肤病为特征的具有明显神经源性炎症的疾病/病症的治疗有用。
