Mechanisms of Inflammation Resolution in Bacterial Endophthalmitis

细菌性眼内炎的炎症消退机制

• 批准号: 10002232
• 负责人: Ashok Kumar
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002232
• 关键词: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibiotics; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Attenuated; Blindness; Bone Marrow; CD59 Antigen; Cataract Extraction; Cells; Co-Immunoprecipitations; Communicable Diseases; Complication; Data; Development; Disease; Docosahexaenoic Acids; Dopamine D1 Receptor; Endophthalmitis; Enzymes; Eye; Eye Infections; FPR2 gene; Gene Silencing; Generations; Genus staphylococcus; Goals; Homeostasis; Human; Immune; Immune response; Immunomodulators; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune Response; Invaded; Knockout Mice; Ligands; Mediating; Mediator of activation protein; Mus; Myeloid Cells; Nature; Older Population; Omega-3 Fatty Acids; Operative Surgical Procedures; Pathway interactions; Penetrating Eye Injuries; Pharmaceutical Preparations; Pharmacology; Procedures; Production; Property; Receptor Signaling; Resolution; Retina; Role; Route; Severities; Signal Pathway; Signal Transduction; Staphylococcus aureus; Staphylococcus aureus infection; Structure; TLR2 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Transgenic Mice; Trauma; Treatment Efficacy; Virulence Factors; Vision; Visual; aging population; bacterial endophthalmitis; base; design; disability; efficacy testing; experimental study; immunomodulatory therapies; improved outcome; inhibitor/antagonist; insight; intravitreal injection; lipid mediator; lipoxin A4; microbial; mouse model; novel; overexpression; pathogen; pre-clinical; preservation; prevent; programmed cell death protein 1; protective effect; receptor; response; restoration; retinal damage; tissue injury; treatment strategy

Project Summary Inflammation is generally considered a beneficial host response towards invading pathogens or tissue injury. Prolonged inflammation, however, can be destructive and maladaptive, leading to irreversible damage to delicate tissues. Thus, the ideal treatment approach when dealing with inflammation-sensitive tissues, such as the retina, should include immunomodulatory therapies to promote the rapid resolution of inflammation and the restoration of tissue homeostasis to minimize secondary host-mediated damage. Recently, pro-resolution- based strategies using specialized pro-resolving mediators (SPMs) have shown great potential for the treatment of multiple inflammatory diseases. We show that the intravitreal administration of resolvin D1 (RvD1), a type of SPM, in bacterial (S. aureus)-infected mouse eyes attenuated the development of endophthalmitis, with drastically reduced inflammation and tissue damage and preserved retinal function, underline the importance of RvD1-mediated pro-resolving signaling in endophthalmitis. However, unexpectedly, we discovered that RvD1 treatment failed to protect the eyes of Toll-like receptor 2 (TLR2) knockout mice from staphylococcal endophthalmitis. Moreover, we observed a direct interaction of TLR2 with the RvD1 receptor, lipoxin A4/formyl peptide receptor 2 (ALX/FPR2, referred as FPR2). This raises an interesting fundamental question, whether the molecule or signaling pathways that induce the resolution of inflammation interact with other pathways such as the TLRs, which promote the induction of inflammation. Thus, based on prior studies and our preliminary data, we hypothesize that RvD1-mediated protective innate responses in bacterial endophthalmitis are dependent on TLR2 signaling. This will be tested with three specific aims. Aim-1 will decipher the mechanisms underlying RvD1-induced protective innate responses in bacterial endophthalmitis. This will be accomplished by using pharmacological inhibitors of RvD1-mediated FPR2 signaling, as well as the use of FPR2 overexpressing transgenic (Tg) mice and FPR2 KO mice. Bone marrow chimeric studies will be performed to determine the relative contribution of FPR2 on residential vs. myeloid cells. Aim-2 will investigate the interplay of the RvD1 and TLR2 signaling pathways in promoting inflammation resolution in endophthalmitis. These studies will elucidate this novel cross-talk by determining 1) whether TLR2 deficiency alters the generation of RvD1, 2) under which conditions TLR2 and FPR2 interact physically, and 3) the consequences of this interaction on downstream signaling. Aim-3 is designed to test the efficacy of RvD1 as an adjunct therapeutic in mitigating endophthalmitis-associated vision loss. Proposed experiments include the co- administration of RvD1 with conventional antibiotics and the determination of the optimal route of delivery (topical vs. intravitreal) and a comparison of its efficacy with that of corticosteroids. Together, we believe that the mechanistic insights and the treatment strategies developed in this proposal could have a major impact on the field, not only with regards to endophthalmitis but other ocular and non-ocular infectious diseases as well.

项目摘要 炎症通常被认为是对入侵病原体或组织损伤的有益宿主反应。 然而，长时间的炎症可能是破坏性的和适应不良的，导致不可逆转的损害 细腻的组织。因此，处理炎症敏感组织时的理想治疗方法，例如 视网膜应包括免疫调节疗法，以促进炎症的快速解决和 恢复组织稳态以最大程度地减少次级宿主介导的损伤。最近，亲分辨率 - 使用专业的支持解决方案（SPM）的基于的策略表现出很大的潜力 多种炎症性疾病的治疗。我们表明，玻璃体内给药Resolvin D1（RVD1）， 一种类型的SPM，在细菌（金黄色葡萄球菌）感染的小鼠眼中减弱了内脑炎的发展， 随着炎症和组织损伤的大幅减少以及保留的视网膜功能，强调 RVD1介导的促链解析信号传导的重要性。但是，出乎意料的是，我们 发现RVD1治疗未能保护像Toll样受体2（TLR2）敲除小鼠的眼睛免受 葡萄球菌内嗜性。此外，我们观察到TLR2与RVD1受体的直接相互作用， Lipoxin A4/甲基肽受体2（ALX/FPR2，称为FPR2）。这提出了一个有趣的基本 问题，诱导炎症分辨率的分子或信号通路是否与 其他途径，例如TLR，促进炎症的诱导。因此，基于先前的研究 和我们的初步数据，我们假设RVD1介导的细菌中的保护性既定反应 内脑膜取决于TLR2信号传导。这将通过三个特定目标进行测试。 AIM-1会 解解了RVD1诱导的细菌性内膜中的保护性先天反应的基础机制。 这将通过使用RVD1介导的FPR2信号的药理抑制剂以及 FPR2过表达的转基因（TG）小鼠和FPR2 KO小鼠的使用。骨髓嵌合研究将 进行以确定FPR2对住宅与髓样细胞的相对贡献。 AIM-2将 研究RVD1和TLR2信号通路的相互作用，以促进炎症分辨率 内脑膜。这些研究将通过确定1）TLR2缺乏症来阐明这种新颖的串扰。 改变rvd1的产生，2）在这种情况下，TLR2和FPR2的身体相互作用，以及3） 这种相互作用在下游信号传导上的后果。 AIM-3旨在测试RVD1的功效 缓解内炎相关的视力丧失的辅助治疗。建议的实验包括 用常规抗生素给予RVD1和确定最佳输送途径 （局部与玻璃体内）及其功效与皮质类固醇的疗效的比较。一起，我们相信 本提案中制定的机械见解和治疗策略可能会对 该领域不仅在内脑炎，而且还有关其他眼和非眼感染疾病。