Targeting keratinocyte cholesterol metabolism to reveal novel mechanisms for treating inflammatory skin disease

项目总结 炎症与大量的急性和慢性皮肤病变有关，它们共同导致了 导致患者和医疗保健负担过重。局部免疫抑制药，如局部皮质类固醇是一线 尽管治疗与皮肤萎缩、纹身和酒渣鼻等无数不良反应有关， 还有其他的。此外，虽然许多炎症性皮肤病涉及相似的免疫激活途径 和疾病的进展，有针对性的抗炎疗法的开发将有助于描绘我们的 了解与皮肤炎症相关的共同和独特的分子机制。 胆固醇对皮肤的正常功能是不可或缺的，最近，过量的细胞内胆固醇已经被 与白介素17A(IL-17A)对培养角质形成细胞的炎症激活有关。有趣的是，这些 这些发现类似于激活的巨噬细胞中发现的依赖胆固醇的炎症过程， 提示角质形成细胞可能受到类似胆固醇调节机制的影响 发炎。因此，需要进行研究来描绘胆固醇代谢和 角质形成细胞引起的炎症。我们实验室首创了一种人工合成的高密度脂蛋白样纳米颗粒(HDL NP)能够通过与B型清道夫受体1特异性结合来调节细胞胆固醇 (SR-B1)，一种负责细胞胆固醇流动的转运蛋白。高密度脂蛋白纳米颗粒在皮肤中的应用是有吸引力的 由于SR-B1在表皮中的广泛存在和高密度脂蛋白良好的物理性质 NPS可使角质形成细胞靶向和定位于表皮的所有层。此外，热门的高密度脂蛋白 在受伤的角膜上皮细胞中给予NP显示了抗炎的好处，进一步 支持胆固醇调节和免疫激活之间的联系。我们的目标是使用高密度脂蛋白NPs作为一种强大的 从机制上研究胆固醇代谢变化如何影响皮肤炎症的工具。我们的 最重要的假设如下：角质形成细胞胆固醇水平控制皮肤中的炎症信号。 在这项研究的第一个目的中，我们将了解高密度脂蛋白NP是如何在 IL-17A激活。在第二个目标中，我们将研究IL-17A依赖的炎症信号在 角质形成细胞在测量已知的趋化物质的表达方面具有特殊的侧重点 使皮肤持久发炎。在这项研究的最终目标中，我们将调查靶向治疗的潜力。 咪喹莫特诱导的银屑病样小鼠皮肤模型体内胆固醇调节的研究 发炎。项目的成功将更好地说明胆固醇代谢在炎症中的作用 皮肤病，开发新的局部疗法来减少炎症。

PROJECT SUMMARY Inflammation is involved in an abundant number of acute and chronic skin pathologies, which together contribute to high patient and healthcare burden. Topical immunosuppressants such as topical corticosteroids are first-line treatments despite their association with a myriad of adverse effects such as skin atrophy, striae, and rosacea, among others. Further, while many inflammatory skin conditions involve similar pathways of immune activation and disease progression, the development of targeted anti-inflammatory therapies would aid in delineating our understanding of the shared and unique molecular mechanisms that accompany inflammation in the skin. Cholesterol is integral to the normal functioning of skin and recently, excess intracellular cholesterol has been associated with inflammatory activation by interleukin-17A (IL-17A) in cultured keratinocytes. Interestingly, these findings resemble the cholesterol-dependent inflammatory processes found in activated macrophages, suggesting keratinocytes could be subjected to similar mechanisms of cholesterol regulation in the setting of inflammation. Therefore, research is required to delineate the relationship between cholesterol metabolism and keratinocyte-induced inflammation. Our lab pioneered a synthetic high-density lipoprotein-like nanoparticle (HDL NP) capable of modulating cellular cholesterol through specifically binding to scavenger receptor class B type 1 (SR-B1), a transporter responsible for cellular cholesterol flux. Application of HDL NPs in the skin is attractive due to the well-established presence of SR-B1 in the epidermis and the favorable physical properties of HDL NPs that may enable keratinocyte targeting and localization to all layers of the epidermis. Further, topical HDL NP administration in wounded corneal epithelial cells has demonstrated anti-inflammatory benefit, further supporting a link between cholesterol modulation and immune activation. We aim to use HDL NPs as a powerful tool to mechanistically study how changes in cholesterol metabolism affect inflammation in the skin. Our overarching hypothesis is the following: keratinocyte cholesterol levels control inflammatory signaling in the skin. In the first aim of the study, we will understand how HDL NP modulates keratinocyte cholesterol in the setting of IL-17A activation. In the second aim, we will investigate IL-17A-dependent inflammatory signaling in keratinocytes with a particular focus in measuring the expression of chemoattractants that are known to perpetuate skin inflammation. In the final aim of the study, we will investigate the therapeutic potential of targeting cholesterol modulation in vivo using the imiquimod-induced psoriasis-like mouse model as a model of skin inflammation. Project success will better delineate the role of cholesterol metabolism in inflammatory skin disease to develop novel topical therapies to reduce inflammation.