Myeloid sphingolipid regulation of tissue resolution and regeneration responses

骨髓鞘脂对组织分辨率和再生反应的调节

• 批准号: 10562518
• 负责人: Timothy Tun Hla
• 金额: $ 57.66万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562518
• 关键词: Acetaminophen; Acute Liver Failure; Agonist; Anti-Inflammatory Agents; Atherosclerosis; Attenuated; Autoimmune Diseases; Biological; Blood Vessels; CXCR4 gene; Cells; Chemicals; Chromatin; Chronic; Complex; Coupled; Cytoplasmic Granules; Data; Development; Disease; Eicosanoids; Engineering; Epithelial; Event; Exhibits; FDA approved; FPR2 gene; Fibrosis; Foundations; Functional disorder; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Goals; Health; Health system; Hematopoietic; Hepatocyte; High Density Lipoproteins; Homeostasis; Homing; Immune; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Knowledge; LTB4R gene; Laboratories; Lead; Liver; Lung; Lysophospholipids; Mediating; Medicine; Methods; Molecular; Molecular Chaperones; Myelogenous; Myeloid Cells; Natural regeneration; Neutrophil Activation; Nuclear; Organ; Pathology; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiology; Play; Process; Prostaglandins; Recovery; Regenerative response; Regulation; Research; Resolution; Role; Seminal; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Vascular Endothelium; Viral; Virus; Virus Diseases; Work; antagonist; attenuation; base; beta-arrestin; body system; chronic inflammatory disease; desensitization; extracellular; innovation; lipid mediator; liver injury; lung injury; lung regeneration; macrophage; mouse genetics; mouse model; neutrophil; novel; novel strategies; novel therapeutic intervention; oxidant stress; particle; programs; receptor; regenerative repair; repaired; response; single-cell RNA sequencing; small molecule; sphingosine 1-phosphate; targeted treatment; tissue injury; tissue regeneration; trafficking; transcriptome

SUMMARY Myeloid cells of the innate immune system (neutrophils and macrophages) interact closely with the vascular endothelium to modulate inflammatory and resolution responses. During early stages of the inflammatory response, inappropriate neutrophils activation causes vascular and parenchymal injury. However, in late stages of inflammation, precisely-controlled neutrophil resolution mechanisms are now considered to be critical to limit tissue damage and initiate regeneration of new vascular channels and parenchymal tissues. Even though neutrophil function in early stages of inflammatory processes is well understood, their involvement in resolution responses is poorly understood. We have found that the sphingosine 1-phosphate (S1P) receptor-1 (S1PR1), a G protein-coupled receptor (GPCR) with well-established functions in vascular and adaptive immune (T and B) cells, regulates neutrophil resolution responses. Specifically, S1PR1 signaling induces a non-inflammatory, long-lived neutrophil phenotype that undergoes efficient phagocytosis. We also found that this novel and unappreciated function of neutrophil S1PR1 signaling axis is critical for efficient recovery from virus-induced lung injury and chemical-induced acute liver failure. To activate this beneficial process, we developed a novel biologic based on our knowledge of S1P chaperones. We hypothesize that local S1PR1 signaling in neutrophils is a general mechanism that resolves inflammatory tissue injury and thus enable vascular and parenchymal regeneration in multiple organ systems. Furthermore, we posit that therapeutic activation of this signaling axis may provide a novel strategy to control chronic smoldering inflammation that lead to fibrotic diseases and organ dysfunction. To test this hypothesis, we will examine GPCR proximal mechanisms and nuclear transcriptional events that are regulated by S1PR1 in tissue neutrophils during resolution responses. Second, we will examine the importance of this signaling axis in resolution responses that are induced after virus-induced lung injury and chemical-induced liver injury in mouse models. Third, we will obtain proof-of-concept data to activate this signaling axis that utilize engineered designer HDL particles that contain ApoA1 and ApoM to stimulate neutrophil resolution responses and enhance vascular endothelial survival and regeneration. These data are anticipated to reveal novel mechanisms of resolution processes and enable innovative therapeutic strategies to control chronic inflammatory diseases.

总结 先天性免疫系统的髓样细胞（中性粒细胞和巨噬细胞）与免疫系统密切相互作用。 血管内皮调节炎症和消退反应。在早期阶段， 炎症反应，不适当的中性粒细胞活化引起血管和实质损伤。 然而，在炎症的晚期阶段，精确控制的中性粒细胞溶解机制现在被破坏。 被认为对限制组织损伤和启动新血管通道的再生至关重要， 实质组织即使中性粒细胞在炎症过程的早期阶段功能良好， 然而，人们对他们参与解决反应的理解却很少。我们发现 1-磷酸鞘氨醇（S1 P）受体-1（S1 PR 1），一种G蛋白偶联受体（GPCR）， 在血管和适应性免疫（T和B）细胞中确立的功能，调节中性粒细胞的溶解 应答具体地，S1 PR 1信号传导诱导非炎性、长寿命的嗜中性粒细胞表型， 进行有效的吞噬作用。我们还发现，中性粒细胞的这一新的和未被重视的功能， S1 PR 1信号传导轴对于病毒诱导的肺损伤和化学诱导的急性肺损伤的有效恢复至关重要。 肝衰竭为了激活这一有益的过程，我们根据对S1 P的了解开发了一种新的生物制剂， 监护人我们假设中性粒细胞中的局部S1 PR 1信号传导是一种通用机制， 炎性组织损伤并因此能够在多器官系统中进行血管和实质再生。 此外，我们认为，治疗激活这一信号轴可能提供一种新的策略，以控制， 慢性阴燃性炎症，导致纤维化疾病和器官功能障碍。为了验证这个假设， 我们将研究GPCR近端机制和S1 PR 1调控的核转录事件 在组织中性粒细胞中。其次，我们将研究这种信号的重要性 在病毒诱导的肺损伤和化学诱导的肝损伤后诱导的分辨反应中， 小鼠模型。第三，我们将获得概念验证数据，以激活这一信号轴， 含有ApoA 1和ApoM以刺激中性粒细胞消退反应的设计HDL颗粒， 增强血管内皮存活和再生。这些数据预计将揭示新的 解决过程的机制，并使创新的治疗策略，以控制慢性 炎症性疾病。