Ceramide Analog Control of Cutaneous Inflammation

屏障功能受损的常见皮肤病代表着巨大的未得到满足的需求， 特别是在非常年轻和不断增加的老年人口中。这些障碍包括 特应性皮炎(7.3%的美国成年人)、牛皮癣(美国人口的2%-3%)、静脉溃疡、淤血 皮炎和光化性角化病。使用润肤剂修复屏障通常用于许多 这些障碍，但只是部分有效。经皮下失水是可以修复的 没有治愈炎症表明特定的生化异常并不是 用简单的润肤剂来解决。在严重炎症性疾病的情况下，如特应性 皮炎和银屑病，许多针对肿瘤坏死因子α，IL-12，IL-17，IL-1β和IL-4的生物制剂已经显示 受益，但这些疗法通常是为10%的最严重的病例保留的，因为副作用 和费用。不太严重的炎症性皮肤病的主要药物仍然是局部类固醇，因为它 在过去的40年里一直如此。其他外用药物，如维甲酸、维生素D和外用 免疫抑制剂的影响较小，因为疗效较差，费用较高。我们的中央 假说是，具有神经酰胺样特性的Solenopsin衍生物可以缓解 炎症，即使面对感染也是如此。我们用新型神经酰胺类似物检验这一假说。 基于蚂蚁毒液中的生物碱Solenopsin，这些物质不会被代谢成促炎物质 鞘氨醇-1磷酸。 一条单一的信号通路可以被抑制来广泛缓解，这可能是违反直觉的 各种疾病，包括由炎症和细菌引起的牛皮癣和特应性皮炎 移居/感染。这说明了这一协议的创新。我们的初步数据显示 证明了外用Solenopsin衍生物在已建立的临床前模型中具有疗效 特应性皮炎(手稿正在准备中)和牛皮癣5。此外，这些研究 独立鉴定的白介素12(IL-12)升高，对外用茄诺菌素类似物的反应。 鉴于IL-12也与传染病有关，因此，一种 单分子可用于治疗皮肤炎症性疾病和感染性疾病。 此外，炎症性和传染性皮肤病的负担高达数百亿美元 每年对易感染的炎症性疾病(皮质类固醇)和 一些抗感染药物具有促炎作用。最后，屏障修复；IL-12连接可能 为解决炎症性和感染性皮肤问题提供一个共同的最终途径。我们的 发现IL-12作为Solenopsin类似物的靶点可能有助于作为疫苗的新型佐剂 发展也是如此。

Common skin disorders with impaired barrier function represent a large and unmet need, especially among both the very young and increasing elderly population. These disorders include atopic dermatitis (7.3% of US adults), psoriasis (2-3% of US population), venous ulcers, stasis dermatitis and actinic keratosis. Barrier restoration with emollients is commonly used for many of these disorders, but is only partially effective. The fact that transepidermal water loss can be repaired without curing the inflammation suggests that specific biochemical abnormalities are not being addressed by simple emollients. In the cases of severe inflammatory disorders, such as atopic dermatitis and psoriasis, many biologics, targeting TNFα, IL-12, IL-17, IL-1β, and IL-4 have shown benefit, but these therapies are usually reserved for the 10% of most severe cases due to side effects and expense. The mainstay of less severe inflammatory skin disorders remains topical steroids, as it has been for the last 40 years. Other topicals, such as retinoids, vitamin D, and topical immunosuppressants have had less impact due to lesser efficacy and greater expense. Our central hypothesis is that solenopsin derivatives, which have ceramide-like properties, can alleviate inflammation, even in the face of infection. We test this hypothesis with novel ceramide analogs based on the ant venom alkaloid solenopsin, which are not metabolized into pro-inflammatory sphingosine-1 phosphate. It may be counterintuitive that a single signaling pathway could be inhibited to alleviate widely different disorders including psoriasis and atopic dermatitis caused by inflammation and bacterial colonization/infection. This speaks to the innovation of this protocol. Our preliminary data have demonstrated that topical solenopsin derivatives have efficacy in well-established preclinical models of atopic dermatitis (manuscript in preparation) and psoriasis 5. Moreover, these studies have independently identified interleukin-12 (IL-12) as elevated in response to topical solenopsin analogs. Given that IL-12 has also been implicated in infectious disease as well, it is therefore feasible that a single molecule could be used in the treatment of both inflammatory and infectious diseases of the skin. In addition, the burden of inflammatory and infectious skin disorders runs into tens of billions of dollars annually with some treatment of inflammatory disorders predisposing to infection (corticosteroids) and some anti-infectives having pro-inflammatory effects. Finally, a barrier restoration; IL-12 link could provide a common final pathway for the resolution of inflammatory and infectious skin conditions. Our discovery of IL-12 as a target of solenopsin analogs could be useful as novel adjuvants for vaccine development as well.