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，导致不可逆的损伤， 脆弱的组织因此，当处理炎症敏感组织时，理想的治疗方法是， 视网膜，应该包括免疫调节疗法，以促进炎症和炎症的快速解决。 恢复组织稳态以使继发性宿主介导的损伤最小化。最近，赞成决议的人- 使用专门的亲解决调解员（SPM）的策略已经显示出巨大的潜力， 治疗多种炎症性疾病。我们表明，玻璃体内注射消退素D1（RvD 1）， 一种SPM，在细菌（S.金黄色葡萄球菌）感染的小鼠眼睛减弱了眼内炎的发展， 炎症和组织损伤显著减少，视网膜功能得以保留， RvD 1介导的促消退信号在眼内炎中的重要性然而，出乎意料的是，我们 发现RvD 1治疗未能保护Toll样受体2（TLR 2）敲除小鼠的眼睛免受 葡萄球菌性眼内炎此外，我们观察到TLR 2与RvD 1受体的直接相互作用， 脂氧素A4/甲酰肽受体2（ALX/FPR 2，简称FPR 2）。这提出了一个有趣的基本原理 问题是，诱导炎症消退的分子或信号通路是否与 其他途径，如TLR，促进炎症的诱导。根据先前的研究， 和我们的初步数据，我们假设RvD 1介导的保护性先天反应，在细菌 眼内炎依赖于TLR 2信号传导。这将通过三个具体目标进行测试。Aim-1将 破译RvD 1诱导的细菌性眼内炎保护性先天反应的机制。 这将通过使用RvD 1介导的FPR 2信号传导的药理学抑制剂以及 使用FPR 2过表达转基因（Tg）小鼠和FPR 2 KO小鼠。骨髓嵌合体研究将 以确定FPR 2对驻留细胞与骨髓细胞的相对贡献。Aim-2将 研究RvD 1和TLR 2信号通路在促进炎症消退中的相互作用， 眼内炎这些研究将通过确定1）TLR 2缺乏是否 改变RvD 1的产生，2）TLR 2和FPR 2物理相互作用的条件，和3） 这种相互作用对下游信号传导的影响。Aim-3旨在测试RvD 1作为一种 减轻眼内炎相关视力丧失的辅助治疗。建议的实验包括共同- RvD 1与常规抗生素的给药以及最佳递送途径的确定 （局部与玻璃体内），并将其疗效与皮质类固醇进行比较。我们相信， 该提案中提出的机制见解和治疗策略可能会对以下方面产生重大影响： 该领域不仅涉及眼内炎，而且涉及其他眼部和非眼部感染性疾病。