RSV-induced M2 macrophage differentiation: role of TLR4/PPARg/RXR signaling axis (80)

RSV 诱导的 M2 巨噬细胞分化：TLR4/PPARg/RXR 信号轴的作用 (80)

基本信息

批准号：
10418803
负责人：
JORGE C BLANCO
金额：
$ 19.01万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-07 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418803
关键词：
2019-nCoV Adoptive Transfer Agonist Anti-Inflammatory Agents Arachidonate 15-Lipoxygenase Bacteria Bacterial Infections Cell Differentiation process Cell Line Cell physiology Child Chimeric Proteins Communicable Diseases Cotton Rats Data Development Elderly Environment Equilibrium Event Exhibits Family Genes Genetic Transcription Goals Gold Heterodimerization Human Immune response In Vitro Individual Infant Infection Inflammation Mediators Inflammatory Influenza Innate Immune Response Interleukin-12 Interleukin-13 Interleukin-4 Invaded Knowledge Laboratories Lead Leukocytes Ligands Lower Respiratory Tract Infection Lung Mediating Mediator of activation protein Metabolic Microbe Modeling Molecular Mucous Membrane Mus Nuclear Hormone Receptors Outcome PPAR gamma PTGS2 gene Pathology Pathway interactions Pattern recognition receptor Persons Phenotype Primary Infection Process Production Publishing Pulmonary Pathology RXR Receptor Signaling Regulation Reporting Research Resolution Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory syncytial virus Role STAT6 gene Seasons Sigmodon Signal Transduction TLR4 gene Testing Therapeutic Tissues Toll-like receptors Translating Vaccination Virus Virus Diseases Wild Type Mouse Work base cyclooxygenase 2 cytokine design effective therapy efficacy testing immunosuppressed in vivo lung injury macrophage member microbial microbicide monocyte new therapeutic target novel therapeutic intervention novel therapeutics pathogen prevent programs promoter receptor binding repaired response rosiglitazone therapeutic target tissue repair tool transcription factor wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Monocytes and macrophages (Mf) sense the presence of pathogens, tissue damage, and host-derived mediators in their environment and respond by differentiating into distinct functional phenotypes that mediate host innate immune responses. For example, “classically activated” (M1) macrophages are highly microbicidal, yet their production of inflammatory mediators may also damage host tissue. At the other end of a functional spectrum, “alternatively activated” (M2) macrophages, induced by IL-4 and IL-13, mediate “wound healing” through elimination of damaged tissue and other anti-inflammatory mechanisms. The Blanco and Vogel laboratories have worked closely together to study the host response to Respiratory Syncytial Virus (RSV), the most significant cause of severe lower respiratory tract infection in infants, the elderly, and immunosuppressed individuals. In wild-type (WT) mice, RSV infection elicits an early, transient M1 Mf re- sponse in the lung that is followed by a more sustained period of M2 Mf predominance and resolution of inflam- matory lung pathology. We reported that IL-4Ra-/- mice, that fail to respond to RSV infection with the development of M2 Mf, exhibit greatly enhanced lung pathology that can be overcome by adoptive transfer of WT Mf that differentiate into M2 Mf upon RSV infection. Importantly, RSV-induced TLR4 signaling was shown to be a pre- requisite for induction of the transcription factor peroxisome proliferator-activated receptor gamma (PPARg). PPARg forms heterodimers with retinoid X receptor (RXR) that bind to M2 Mf gene promoters and activate tran- scription of M2 Mf genes. Our primary objective in this R21 application is to define in greater detail mechanisms governing the TLR4-induced PPARg/RXR signaling axis and the consequences of M2 Mf in the resolution of RSV infection. The overarching hypothesis to be tested is that the balance of M1 and M2 Mf during RSV infection dictates the extent of RSV disease. By comparing the responses of WT mice and mice with PPARg-deficient Mf in vivo and in vitro, we will determine the role of TLR4-induced PPARg/RXR axis in the regulation of M2 Mf development in RSV (Specific Aim 1). In Specific Aim 2, Targeting the TLR4-induced PPARg/RXR signal- ing axis in the cotton rat model of RSV, we will extend our findings using cotton rats, the gold standard for development of RSV therapies, to test the hypothesis that therapeutic administration of PPARg and RXR agonists to infected cotton rats will result in synergistic M2 Mf differentiation that, in turn, will mitigate inflammatory lung damage normally caused by RSV infection. These two aims are based on our strong published and preliminary data, and support the concept that the balance between M1 Mf-mediated inflammatory lung damage and PPARg/RXR-driven transcription of M2 Mf genes, leading to tissue repair, dictates the ultimate outcome. At the conclusion of these exploratory studies, key processes that lead to changes in Mf activation will have been defined that, in turn, are expected to translate into reasonable and practical therapeutic approaches for counter- acting inflammatory lung damage induced by RSV, and possibly other agents (e.g., influenza, SARS-CoV-2).

项目概要/摘要单核细胞和巨噬细胞 (Mf) 感知病原体、组织损伤和宿主来源的存在环境中的介质并通过分化成不同的功能表型来做出反应例如，“经典激活”（M1）巨噬细胞具有很强的杀菌能力，然而，它们产生的炎症介质也可能损害宿主组织的功能。谱中，IL-4 和 IL-13 诱导的“交替激活”(M2) 巨噬细胞介导“伤口愈合” 通过消除受损组织和其他抗炎机制。布兰科和沃格尔实验室密切合作，研究宿主对呼吸道疾病的反应合胞病毒（RSV）是婴儿、老年人、儿童严重下呼吸道感染的最重要原因。在野生型 (WT) 小鼠和免疫抑制个体中，RSV 感染会引发早期、短暂的 M1 Mf 反应。肺部反应，随后是 M2 Mf 占主导地位的更持续时期和炎症消退 - 我们报道了 IL-4Ra-/- 小鼠在发育过程中对 RSV 感染没有反应。 M2 Mf 的肺部病理学表现出极大增强，可以通过 WT Mf 的过继转移来克服重要的是，RSV 诱导的 TLR4 信号转导被证明是一种预-RSV 感染。诱导转录因子过氧化物酶体增殖物激活受体γ (PPARg) 所必需的。 PPARg 与类视黄醇 X 受体 (RXR) 形成异二聚体，RXR 结合 M2 Mf 基因启动子并激活反式 M2 Mf 基因的描述我们在此 R21 应用中的主要目标是更详细地定义机制。控制 TLR4 诱导的 PPARg/RXR 信号轴以及 M2 Mf 在分辨率中的影响 RSV 感染需要检验的首要假设是 RSV 感染期间 M1 和 M2 Mf 的平衡。通过比较 WT 小鼠和 PPARg 缺陷型 Mf 小鼠的反应来确定 RSV 疾病的程度。在体内和体外，我们将确定TLR4诱导的PPARg/RXR轴在M2 Mf调节中的作用 RSV 的开发（具体目标 1），在具体目标 2 中，针对 TLR4 诱导的 PPARg/RXR 信号。由于RSV棉鼠模型中的轴，我们将使用棉鼠来扩展我们的发现，棉鼠是RSV的黄金标准 RSV 疗法的开发，以检验 PPARg 和 RXR 激动剂治疗性给药的假设对受感染的棉鼠进行治疗将导致协同 M2 Mf 分化，从而减轻肺部炎症通常由 RSV 感染造成的损害这两个目标是基于我们强有力的已发表的和初步的。数据，并支持 M1 Mf 介导的炎症性肺损伤与 PPARg/RXR 驱动的 M2 Mf 基因转录导致组织修复，决定了最终结果。根据这些探索性研究的结论，导致 Mf 激活变化的关键过程将是定义，反过来，预计将转化为合理和实用的治疗方法，以对抗 RSV 以及可能的其他病原体（例如流感、SARS-CoV-2）引起的炎症性肺部损伤。