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 紫外线辐射(UVR)是对皮肤最常见的环境侮辱，它是一种普遍存在的致癌物质。 皮肤UVB暴露可启动色素沉着级联反应，并上调Pro-2的表达 表皮角质形成细胞中的阿片黑素皮质素(POMC)。POMC在翻译后被切割为Year 黑素皮质肽是刺激产生保护性黑色素所必需的。有趣的是，卵裂 POMC还产生内源性阿片类药物β-内啡肽(β-End)，导致血浆全身性增加 β-END水平足以引起小鼠的晒黑成瘾。 Β-END是一种内源性阿片类药物，它与中枢神经系统表达的微阿片受体结合。 和周围神经系统(CNS、PNS)。虽然阿片类药物的止痛作用是公认的，但 在动物模型中已经证明了抑制炎症的作用。我们观察到β-End的损失 或µ-OPR在小鼠中导致对UVB的严重皮肤炎反应提示阿片类药物抑制 皮肤发炎。 我们推测UVR诱导的β-END可能具有急性有益效应。这项提议将澄清 阿片类药物信号的局部、皮肤效应和整体、全身效应对 皮肤发炎。目的1建立实验性晒伤条件，研究阿片类药物的作用 在皮肤炎症中使用具有和不具有功能阿片信号的小鼠。除了研究 β-END在紫外线照射后的作用，我们将确定β-END是否能抑制皮肤炎症 炎症状态，如特应性皮炎和牛皮癣。最后，使用组织病理学分析和 流式细胞仪技术，我们将表征β-End KO、µ-OPR KO和 C57BL6小鼠，以确定皮肤表型的促成因素。 在目标2中，我们将探讨β-END发挥抗炎作用的机制。我们 假设角质形成细胞衍生的β-内啡肽作用于免疫细胞和周围神经纤维 抑制炎症。利用小鼠模型，我们将免疫表型阿片类药物缺乏的小鼠与对照组 以确定基线和紫外线照射条件下小鼠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µ-OPR的表达是否足以影响 紫外线照射后的皮肤炎症反应。最后，为了区分 中枢神经系统和三七总皂苷对阿片类药物的抗炎作用，我们将发掘其药理调控作用。 阿片信号通路。综合起来，这些研究可能揭示临床上相关的应用和机制。 外用外周作用的阿片类药物作为几种皮肤的抗炎治疗 炎症状态。

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.