Ceramide Analog Control of Cutaneous Inflammation

屏障功能受损的常见皮肤疾病是一个巨大而未满足的需求，

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.