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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的人类每天都会受到多种且常常同时发生的环境压力的影响。这些物质之间的相互作用仍然是一个尚未得到充分研究的领域。值得注意的是，紫外线辐射 (UVR) 具有深远的影响。对皮肤产生影响，并产生从发烧到免疫抑制再到维生素 D 等全身性后果 UVR 具有作为免疫抑制剂和诱变剂的能力，使得这种环境剂成为可能。成为一种完全致癌物，并且是非黑色素瘤皮肤癌和黑色素瘤的原因。环境污染物中，多环芳烃（PAH）无处不在，并发挥免疫调节作用以及致癌作用，很大程度上是通过充当芳基烃受体 (AHR) 的激动剂。然而，对于 UVR 和污染物（特别是 UVB）之间的相互作用存在重大的知识差距。由于仅穿透表皮，光生物学的一个主要问题是经过 UVB 处理的皮肤如何发送系统信号。最近的研究表明，称为微泡颗粒（MVP）的小膜结合囊泡细胞响应各种压力而释放的信号分子可以作为有效的信号剂，因为它们能够携带我们已经证明 UVB（而非 UVA）会产生 MVP 释放。上皮细胞和皮肤，这可以为 UVB 介导的系统信号传导提供潜在机制。小组和其他人已经证明 UVB（不是 UVA）会产生高水平的脂质介质血小板活化酶促产生的因子 (PAF) 和通过活性氧非酶促产生的氧化 PAF 激动剂最近的研究使用 PAFR 表达/无效细胞系和药理学/遗传抑制 ROS 和酸性鞘磷脂酶 (aSMase) 表明 PAF 受体参与其中 (PAFR) 信号传导导致 UVB 生成 MVP (UVB-MVP) 中 aSMase 激活。 UVB-MVP 携带生物活性 PAF 激动剂，我们捕获它介导延迟的免疫抑制作用重要的是，我们发现 PAH 苯并[a]芘 (BaP) 与 UVB 相互作用会释放出高水平的 UVB。计划有两个目标来检验以下假设： BaP+UVR（UVA 与 UVB）协同产生 ROS，生成 PAF 和 UVR-MVP 以独立于 AHR 的方式增强全身免疫抑制，目标 1 将使用体外细胞系，例如。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 的生成，并使用以下方法定义 BaP 与 UVR 协同作用中 PAFR 的作用发射 UVA 和 UVB 能量的模拟太阳光 (SSL) 源将定义增强型的作用。 BaP 产生 UVB-MVP 以及 Tregs 和细胞因子（包括 IL-10 和 TGFβ）的参与延迟该项目的成功完成将（i）定义一种新的机制，通过该机制 PAH 污染物可以增强紫外线引起的影响；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信号传导效应。