Mechanisms of augmented UVB immunosuppressive responses by polyaromatic hydrocarbons

多环芳烃增强 UVB 免疫抑制反应的机制

• 批准号: 10527648
• 负责人: Ravi PRAKASH Sahu
• 金额: $ 22.5万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527648
• 关键词: Address; Agonist; Antioxidants; Area; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Benzo(a)pyrene; Biological Models; Carbon Black; Carcinogens; Cell Line; Cells; Complex; Contact hypersensitivity; Dose; Environmental Pollutants; Environmental Pollution; Enzymes; Epidermis; Epithelial Cells; Exposure to; Fever; Generations; Genetic; Goals; Human; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Interleukin-10; Knowledge; Laboratories; Light; Measures; Mediating; Membrane; Metabolic; Modeling; Molecular; Mus; Mutagens; Nuclear; Null Lymphocytes; Outcome; Oxides; Pathologic; Penetration; Pharmacology; Photobiology; Physiological; Platelet Activating Factor; Play; Process; Production; Publishing; Reaction; Reactive Inhibition; Reactive Oxygen Species; Receptor Signaling; Regulatory T-Lymphocyte; Role; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Source; Stimulus; Sunlight; Systems Analysis; Techniques; Testing; Tissues; Transforming Growth Factor beta; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Vesicle; Vitamin D; Work; acid sphingomyelinase; cancer risk; carcinogenicity; chromophore; cytokine; environmental agent; environmental stressor; fire fighter; human subject; immunoregulation; in vivo; inhibitor; insight; keratinocyte; lipid mediator; mast cell; melanoma; microvesicles; novel; novel strategies; particle; platelet activating factor receptor; pollutant; response; skin cancer prevention; solar ultraviolet radiation; stressor; synergism; tool; ultraviolet

Abstract Humans are subjected daily to multiple and often simultaneous environmental stressors. Yet the complex interaction of these agents remains an understudied area. Notably, ultraviolet radiation (UVR) has profound effects on the skin and generates systemic consequences from fever to immunosuppression to vitamin D production. The ability of UVR to act as both immunosuppressant and mutagen allows this environmental agent to become a complete carcinogen and is the cause for non-melanoma skin cancer and melanoma. Besides, environmental pollutants, polycyclic aromatic hydrocarbons (PAH) are ubiquitous and exert immunomodulatory as well as pro-carcinogenic effects, in great part via acting as agonists for the aryl hydrocarbon receptor (AHR). However, there is a significant knowledge gap of interactions between UVR and pollutants. In particular, as UVB only penetrates the epidermis, a major question in photobiology is how UVB-treated skin sends systemic signals. Recent studies have indicated that small membrane-bound vesicles known as microvesicle particles (MVP) released from cells in response to various stressors can act as potent signaling agents due to their ability to carry nuclear and cytoplasmic components. We have demonstrated that UVB (not UVA) generates MVP release from epithelial cells and skin, which could provide a potential mechanism for UVB-mediated systemic signaling. Our group and others have shown that UVB (not UVA) generates high levels of the lipid mediator Platelet-activating factor (PAF) produced enzymatically and oxidized PAF agonists produced non-enzymatically via reactive oxygen species (ROS). Recent studies using PAFR-expressing/null cell lines and pharmacologic/genetic inhibition of ROS, and the enzyme acid sphingomyelinase (aSMase) have implicated the involvement of the PAF-receptor (PAFR) signaling resulting in aSMase activation in UVB generated MVP (UVB-MVP). We provide evidence that UVB-MVP carry bioactive PAF agonists, which we hypothesize mediate the delayed immunosuppressive effects of UVB. Importantly, we discovered that the PAH Benzo[a]pyrene (BaP) interaction with UVB releases high levels of UVB-MVP and generate increased levels of PAF agonists. Two aims are planned to test the hypothesis that BaP+UVR (UVA vs UVB) results in a synergistic production of ROS that generate PAF and UVR-MVP resulting in enhanced systemic immunosuppression in an AHR-independent manner. Aim 1 will use in vitro cell lines, ex vivo skin explants and in vivo murine genetic and pharmacologic models to determine the mechanisms of BaP augmentation of UVB-MVP and PAF generation as well as define PAFR role in BaP synergy with UVR using a simulated solar light (SSL) source that emits both UVA and UVB fluences. Aim 2 will define the roles of enhanced UVB-MVP generation by BaP and the involvement of Tregs and cytokines, including IL-10 and TGFβ in delayed immunosuppressive effects. Successful completion of this project will (i) define a novel mechanism by which a PAH pollutant can augment UVR-induced effects; and ii) address an important question in photobiology as to how a keratinocyte-specific stimulus can generate systemic signaling effects.

摘要 人类每天都受到多种且往往同时发生的环境压力。然而， 这些药物的相互作用仍然是一个研究不足的领域。值得注意的是，紫外线辐射（UVR）具有深刻的 对皮肤产生影响，并产生从发热到免疫抑制到维生素D的全身性后果 生产紫外线辐射作为免疫抑制剂和诱变剂的能力使得这种环境因子 成为一种完全的致癌物质，是非黑色素瘤皮肤癌和黑色素瘤的原因。此外，我们认为， 环境污染物，多环芳烃（PAH）是普遍存在的，并发挥免疫调节作用 以及促癌作用，在很大程度上通过作为芳烃受体（AHR）的激动剂。 然而，有一个显着的知识差距之间的相互作用紫外线和污染物。特别是UVB 紫外线只能穿透表皮，光生物学的一个主要问题是紫外线处理过的皮肤如何发送系统信号。 最近的研究表明，小的膜结合囊泡称为微泡颗粒（MVP） 细胞对各种应激源的反应中释放出的蛋白质可以作为有效的信号传导剂， 细胞核和细胞质成分。我们已经证明，UVB（不是UVA）产生MVP释放， 上皮细胞和皮肤，这可能提供了一个潜在的机制UVB介导的系统信号。我们 小组和其他人已经表明，UVB（而不是UVA）产生高水平的脂质介质血小板活化 酶促产生的PAF和通过活性氧非酶促产生的氧化PAF激动剂 物种（ROS）。使用PAFR表达/无效细胞系和PAFR的药理学/遗传学抑制的最新研究 ROS和酸性鞘磷脂酶（aSMase）涉及PAF受体的参与。 在UVB产生的MVP（UVB-MVP）中，PAFR信号传导导致aSM酶活化。我们提供的证据表明， UVB-MVP携带有生物活性的PAF激动剂，我们推测其介导了延迟的免疫抑制作用 的UVB。重要的是，我们发现PAH苯并[a]芘（BaP）与UVB的相互作用释放出高水平的 并产生增加的PAF激动剂水平。计划有两个目标来检验这一假设， BaP+UVR（UVA vs UVB）导致产生PAF和UVR-MVP的ROS的协同产生， 以不依赖AHR的方式增强全身免疫抑制。Aim 1将使用体外细胞系， 体内皮肤外植体和体内小鼠遗传和药理学模型，以确定BaP的机制 增强UVB-MVP和PAF的产生，并使用一种新的方法确定PAFR在BaP与UVR协同作用中的作用。 模拟太阳光（SSL）源，发射UVA和UVB通量。目标2将界定增强的 BaP引起的UVB-MVP的产生以及T细胞因子和细胞因子（包括IL-10和TGFβ）的参与， 免疫抑制作用。该项目的成功完成将（i）确定一个新的机制， 多环芳烃污染物可以增加紫外线辐射引起的影响;和ii）解决光生物学中的一个重要问题， 角质形成细胞特异性刺激如何产生系统性信号传导效应。