The role of beta-endorphin in cutaneous inflammation

项目摘要 皮肤是人体最大的器官，是抵御环境的屏障。一 对皮肤最常见的环境损害是紫外线辐射（UVR），一种普遍存在的致癌物。 皮肤UVB暴露引发色素沉着级联反应， 阿黑皮素（POMC）在表皮角质形成细胞。POMC是后裂解的， 黑皮质素肽对刺激保护性黑色素的产生至关重要。有趣的是， POMC还产生内源性阿片类药物β-内啡肽（β-末端），导致血浆中的全身性增加 β-末端的水平足以引起小鼠的“晒黑成瘾”。 Β-末端是一种内源性阿片样物质，与中枢神经系统中表达的μ-阿片样受体（μ-OPR）结合。 和外周神经系统（CNS，PNS）。虽然阿片类药物的镇痛作用已经得到很好的证实， 在抑制炎症中的作用已在动物模型中得到证实。我们观察到β-末端的缺失 或µ-OPR在小鼠中导致对UVB的严重皮肤炎症反应，表明阿片类药物抑制了 皮肤发炎。 我们推测UVR诱导的β-end可能具有急性有益作用。这一建议将阐明 阿片样物质信号传导的局部、皮肤效应和全局、全身效应对 皮肤炎症目的1将建立实验“晒伤”条件，以研究阿片类药物的作用 在有和没有阿片样物质信号传导的小鼠皮肤炎症中。除了研究 β-end在UVR后的作用，我们将确定β-end是否抑制皮肤炎症模型中的皮肤炎症。 炎性病症，如特应性皮炎和牛皮癣。最后，使用组织病理学分析和 流式细胞术技术，我们将表征β-末端KO、µ-OPR KO和 C57 BL 6小鼠，以鉴定皮肤表型的促成因素。 目的2：探讨β-end发挥抗炎作用的机制。我们 假设角化细胞衍生的β-内啡肽作用于免疫细胞和外周神经纤维， 抑制炎症。使用小鼠模型，我们将免疫表型阿片样物质缺陷小鼠和对照 小鼠，以确定在基线和UV暴露条件下免疫细胞的差异数量。接下来，使用 骨髓移植，我们将确定免疫细胞上的µ-OPR表达是否足以影响 对UVR的皮肤炎症反应。最后，为了区分潜在的贡献， CNS和PNS对阿片类药物抗炎作用的影响，我们将利用药理学操作， 阿片信号通路结合起来，这些研究可能会揭示临床相关的应用和机制 局部应用，外周作用阿片类药物作为抗炎治疗的几个皮肤 炎性条件。

Project Summary The skin is the largest organ of the human body and serves as a barrier against the environment. One of the most common environmental insults to the skin is ultraviolet radiation (UVR), a ubiquitous carcinogen. Cutaneous UVB exposure initiates the pigmentation cascade, with the upregulation of pro- opiomelanocortin (POMC) in epidermal keratinocytes. POMC is post-translationally cleaved to yield melanocortin peptides essential for stimulating production of protective melanin. Interestingly, cleavage of POMC also yields the endogenous opioid, β-endorphin (β-end), leading to a systemic increase in plasma levels of β-end that is sufficient to cause `tanning addiction' in mice. Β-end is an endogenous opioid that binds to the µ-opioid receptor (µ-OPR) expressed in the central and peripheral nervous systems (CNS, PNS). Though the analgesic effects of opioids are well established, a role in suppressing inflammation has been demonstrated in animal models. Our observation that loss of β-end or µ-OPR in mice results in a severe cutaneous inflammatory response to UVB suggests that opioids suppress inflammation in the skin. We hypothesize that UVR-induced β-end may have acute beneficial effects. This proposal will elucidate the contribution of both the local, cutaneous effects, and the global, systemic, effects of opioid signaling on cutaneous inflammation. Aim 1 will establish the experimental `sunburn' conditions to study the role of opioids in cutaneous inflammation using mice with and without functioning opioid signaling. In addition to studying the role of β-end after UVR, we will determine if β-end suppresses cutaneous inflammation in models of cutaneous inflammatory conditions, such as atopic dermatitis and psoriasis. Lastly, using histopathological analysis and flow cytometry techniques, we will characterize the local inflammatory response in β-end KO, µ-OPR KO, and C57BL6 mice to identify contributing factors to the cutaneous phenotype. In Aim 2 we will explore the mechanism by which β-end exerts its anti-inflammatory effects. We hypothesize that keratinocyte-derived β-endorphin acts on immune cells and peripheral nerve fibers to suppress inflammation. Using the murine model, we will immunophenotype opioid-deficient mice and control mice to determine differential numbers of immune cells in baseline and UV-exposed conditions. Next, using bone marrow transplantation, we will determine if expression of µ-OPR on immune cells is sufficient to affect the cutaneous inflammatory response to UVR. Lastly, to distinguish between potential contributions of the CNS and PNS to the anti-inflammatory effects of opioids, we will exploit pharmacological manipulation of the opioid signaling pathway. Combined, these studies may reveal a clinically relevant application and mechanism of topically-applied, peripherally-acting opioids as anti-inflammatory treatments for several cutaneous inflammatory conditions.