PDF(Pubmed)
Abstract：
Psoriasis is characterized by intense pruritus, with a subset of individuals with psoriasis experiencing thermal hypersensitivity. However, the pathophysiology of thermal hypersensitivity in psoriasis and other skin conditions remains enigmatic. Linoleic acid is an omega-6 fatty acid that is concentrated in the skin, and oxidation of linoleic acid into metabolites with multiple hydroxyl and epoxide functional groups has been shown to play a role in skin barrier function. Previously, we identified several linoleic acid‒derived mediators that were more concentrated in psoriatic lesions, but the role of these lipids in psoriasis remains unknown. In this study, we report that two such compounds-9,10-epoxy-13-hydroxy-octadecenoate and 9,10,13-trihydroxy-octadecenoate-are present as free fatty acids and induce nociceptive behavior in mice but not in rats. By chemically stabilizing 9,10-epoxy-13-hydroxy-octadecenoate and 9,10,13-trihydroxy-octadecenoate through the addition of methyl groups, we observed pain and hypersensitization in mice. The nociceptive responses suggest an involvement of the TRPA1 channel, whereas hypersensitive responses induced by these mediators may require both TRPA1 and TRPV1 channels. Furthermore, we showed that 9,10,13-trihydroxy-octadecenoate‒induced calcium transients in sensory neurons are mediated through the Gβγ subunit of an unidentified G-protein coupled receptor (GPCR). Overall, mechanistic insights from this study will guide the development of potential therapeutic targets for the treatment of pain and hypersensitivity.
摘要：
牛皮癣的特点是剧烈瘙痒，一部分牛皮癣患者患有热超敏反应。然而,牛皮癣和其他皮肤疾病的热超敏反应的病理生理学仍然是个谜。亚油酸是一种浓缩在皮肤中的omega-6脂肪酸，并将亚油酸氧化成具有多个羟基和环氧官能团的代谢物已被证明在皮肤屏障功能中起作用。以前,我们确定了几种亚油酸衍生的介质，它们更集中在银屑病皮损中，但这些脂质在牛皮癣中的作用尚不清楚。在这项研究中,我们报道了两种这样的化合物-9,10-环氧-13-羟基-十八烯酸酯和9,10,13-三羟基-十八烯酸酯-作为游离脂肪酸存在，并在小鼠中而不是在大鼠中诱导伤害性行为。通过添加甲基使9,10-环氧-13-羟基-十八烯酸酯和9,10,13-三羟基-十八烯酸酯化学稳定，我们观察到小鼠的疼痛和超敏反应。伤害性反应提示TRPA1通道参与，而由这些介质诱导的超敏反应可能需要TRPA1和TRPV1通道。此外，我们表明，9,10,13-三羟基十八烯酸诱导的感觉神经元钙瞬变是通过未识别的G蛋白偶联受体（GPCR）的Gβγ亚基介导的。总的来说,本研究的机械见解将指导开发治疗疼痛和超敏反应的潜在治疗靶点.
