Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
Departments of Anatomy and Neurobiology, Pharmacology, and Biological Chemistry, University of California, Irvine, California, USA.
J Invest Dermatol. 2018 Mar;138(3):562-569. doi: 10.1016/j.jid.2017.07.853. Epub 2017 Oct 18.
N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase highly expressed in macrophages and B lymphocytes, catalyzes the degradation of palmitoylethanolamide. Palmitoylethanolamide is an agonist of PPAR-α and an important regulator of pain and innate immunity. In this study, we investigated the properties of the NAAA inhibitor, ARN077, in a mouse model of allergic contact dermatitis. Acute topical applications of ARN077 attenuated key signs of DNFB-induced dermatitis in a dose-dependent manner. Moreover, ARN077 increased tissue palmitoylethanolamide content and normalized circulating levels of cytokines and immunoglobulin E. No such effect was seen in PPAR-α-deficient mice. Moreover, mice lacking NAAA failed to develop edema or scratching behavior after challenge with DNFB, confirming that this enzyme plays an important role in dermatitis. Consistent with this conclusion, subchronic applications of ARN077 suppressed DNFB-induced inflammation when administered either before or after the DNFB challenge. The effects of subchronic ARN077 were dose dependent and comparable in size to those produced by the steroids clobetasol and dexamethasone. Unlike the latter, however, ARN077 did not cause skin atrophy. The results identify NAAA as a promising target for the development of effective and safe treatments for atopic dermatitis and other inflammatory disorders of the skin.
N-酰基乙醇胺水解酶（NAAA）是一种半胱氨酸水解酶，在巨噬细胞和 B 淋巴细胞中高度表达，能够催化棕榈酰乙醇酰胺的降解。棕榈酰乙醇酰胺是过氧化物酶体增殖物激活受体-α（PPAR-α）的激动剂，也是疼痛和先天免疫的重要调节剂。在本研究中，我们研究了 NAAA 抑制剂 ARN077 在变应性接触性皮炎小鼠模型中的特性。急性局部应用 ARN077 可剂量依赖性减轻 DNFB 诱导的皮炎的关键体征。此外，ARN077 增加了组织中棕榈酰乙醇酰胺的含量，并使循环细胞因子和免疫球蛋白 E 水平正常化。在 PPAR-α 缺陷小鼠中未观察到这种作用。此外，缺乏 NAAA 的小鼠在接受 DNFB 挑战后不会发生水肿或搔抓行为，这证实了该酶在皮炎中起着重要作用。与这一结论一致的是，ARN077 的亚慢性应用在 DNFB 挑战之前或之后给药均可抑制 DNFB 诱导的炎症。亚慢性 ARN077 的作用呈剂量依赖性，与类固醇氯倍他索和地塞米松产生的作用相当。然而，与后者不同的是，ARN077 不会导致皮肤萎缩。这些结果表明 NAAA 是开发有效和安全的特应性皮炎和其他皮肤炎症性疾病治疗方法的有前途的靶点。
