Nakagawa Yutaka, Yamada Shizuo
Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan
Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan.
J Pharmacol Exp Ther. 2023 May;385(2):78-87. doi: 10.1124/jpet.122.001482. Epub 2023 Feb 24.
Atopic dermatitis is a common chronic inflammatory skin disease, with most cases experiencing skin barrier dysfunction and enhanced allergen entry, accompanied by cytokine production which evokes predominantly type-2-skewed immune responses, itch, and scratching behavior. Although intense itch and excessive scratching behavior affect progression of skin lesions, it is unclear what causes them. Data suggest that scratching behavior stimulates brain dopaminergic reward and habit learning systems, strengthening habitual scratching behavior, while nocturnal scratching behavior presumably increases locus coeruleus-noradrenergic system activity, prompting sleep disturbances. At the early stage of atopic dermatitis, increased cortisol levels, due to hypothalamic-pituitary-adrenal axis overactivation caused by such system stimulation, can induce dorsolateral prefrontal cortex disturbance with reinforcement of habitual scratching behavior and may aggravate type-2-skewed immune responses in the skin. During the later phases, whereas blunted hypothalamic-pituitary-adrenal axis function and the shift of type-2-dominated to type-1-co-dominated inflammation are induced, noradrenergic system overactivation-associated dorsolateral prefrontal cortex disruption is ongoing and responsible for itch cognitive distortion to catastrophize about itch, which leads to a vicious spiral along with habitual scratching behavior and skin lesions. Data are presented in this review indicating that while skin immune system dysfunction initiates pathologic changes in atopic dermatitis, brain neural network and stress system alterations can promote the progression of this condition. It is also suggested that cognitive distortion contributes to pathology in atopic dermatitis as with some psychiatric disorders and chronic pain. The proposed mechanistic model could lead to development of novel medications for slowing or terminating the relentless progression of this disorder. SIGNIFICANCE STATEMENT: Although conventional pharmacological interventions focusing on skin homeostasis and itch occurrence significantly attenuate clinical signs in atopic dermatitis patients, achievement of 100% improvement is less than 40% in several double-blind, randomized, placebo-controlled trials. Our model predicts that itch cognitive distortion, due to dorsolateral prefrontal cortex disturbance, can significantly contribute to the progression of atopic dermatitis and that agents capable of improving brain neural network, stress system, and skin homeostasis may be effective as interventions in the treatment of this condition.
特应性皮炎是一种常见的慢性炎症性皮肤病，大多数病例存在皮肤屏障功能障碍和变应原进入增加的情况，同时伴有细胞因子产生，这主要引发2型偏向的免疫反应、瘙痒和搔抓行为。尽管强烈的瘙痒和过度的搔抓行为会影响皮肤病变的进展，但尚不清楚其病因。数据表明，搔抓行为会刺激大脑多巴胺能奖赏和习惯学习系统，强化习惯性搔抓行为，而夜间搔抓行为可能会增加蓝斑-去甲肾上腺素能系统的活动，导致睡眠障碍。在特应性皮炎的早期，由于这种系统刺激导致下丘脑-垂体-肾上腺轴过度激活，皮质醇水平升高，可诱发背外侧前额叶皮质功能紊乱，强化习惯性搔抓行为，并可能加重皮肤中的2型偏向免疫反应。在后期，虽然会诱发下丘脑-垂体-肾上腺轴功能迟钝以及炎症从以2型为主转变为1型和2型共同主导，但与去甲肾上腺素能系统过度激活相关的背外侧前额叶皮质破坏仍在持续，并导致对瘙痒的认知扭曲，进而导致与习惯性搔抓行为和皮肤病变形成恶性循环。本综述中的数据表明，虽然皮肤免疫系统功能障碍引发了特应性皮炎的病理变化，但大脑神经网络和应激系统的改变会促进该病的进展。还表明，认知扭曲与某些精神疾病和慢性疼痛一样，在特应性皮炎的病理过程中起作用。所提出的机制模型可能会促使开发新型药物，以减缓或终止这种疾病的持续进展。意义声明：尽管专注于皮肤稳态和瘙痒发生的传统药物干预措施可显著减轻特应性皮炎患者的临床症状，但在几项双盲、随机、安慰剂对照试验中，实现100%改善的比例不到40%。我们的模型预测，由于背外侧前额叶皮质功能紊乱导致的瘙痒认知扭曲，可显著促进特应性皮炎的进展，而能够改善大脑神经网络、应激系统和皮肤稳态的药物可能作为治疗这种疾病的有效干预措施。
