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: 10708956
• 负责人: Timothy Tun Hla
• 金额: $ 58.97万
• 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/10708956
• 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; Epithelium; Event; Exhibits; FDA approved; FPR2 gene; Fibrosis; Foundations; Functional disorder; G protein coupled receptor kinase; G-Protein-Coupled Receptors; 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; Liver; Lung; Lysophospholipids; Macrophage; Mediating; Medicine; Methods; Molecular; Molecular Chaperones; Myelogenous; Myeloid Cells; Natural regeneration; Neutrophil Activation; Nuclear; Organ; Pathology; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Phase; Phenotype; Physiology; Play; Process; Prostaglandins; Recovery; Regenerative response; Regulation; Research; Resolution; Role; Seminal; Signal Induction; Signal Transduction; Sphingolipids; Sphingosine-1-Phosphate Receptor; Testing; Therapeutic; Tissues; Transgenic Mice; Vascular Endothelium; Viral; Virus; Virus Diseases; Work; antagonist; attenuation; beta-arrestin; body system; chronic inflammatory disease; desensitization; extracellular; inflammatory modulation; innovation; lipid mediator; liver injury; lung injury; lung regeneration; mouse genetics; mouse model; neutrophil; novel; novel strategies; novel therapeutic intervention; oxidant stress; particle; pharmacologic; programs; receptor; regenerative; repaired; response; single-cell RNA sequencing; small molecule; sphingosine 1-phosphate; synergism; 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.

概括 先天免疫系统的骨髓细胞（中性粒细胞和巨噬细胞）与 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激活导致血管和实质损伤。 然而，在炎症的晚期阶段，精确控制的中性粒细胞分解机制现在已成为可能。 被认为对于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。尽管中性粒细胞在炎症过程早期的功能良好 人们对他们参与决议响应的了解却知之甚少。我们发现 1-磷酸鞘氨醇 (S1P) 受体-1 (S1PR1)，一种 G 蛋白偶联受体 (GPCR) 血管和适应性免疫（T 和 B）细胞中完善的功能，调节中性粒细胞分辨率 回应。具体来说，S1PR1 信号传导诱导非炎症性、长寿命的中性粒细胞表型， 进行有效的吞噬作用。我们还发现中性粒细胞的这种新颖且未被重视的功能 S1PR1 信号轴对于病毒引起的肺损伤和化学物质引起的急性肺损伤的有效恢复至关重要 肝功能衰竭。为了激活这一有益过程，我们根据 S1P 知识开发了一种新型生物制剂 伴侣。我们假设中性粒细胞中的局部 S1PR1 信号传导是解决以下问题的通用机制： 炎症组织损伤，从而使多个器官系统中的血管和实质再生。 此外，我们认为该信号轴的治疗激活可能提供一种新的策略来控制 导致纤维化疾病和器官功能障碍的慢性闷烧炎症。为了检验这个假设， 我们将检查受 S1PR1 调节的 GPCR 近端机制和核转录事件 在解决反应期间组织中性粒细胞中。其次，我们将研究该信号的重要性 病毒引起的肺损伤和化学物质引起的肝损伤后诱导的分辨率反应轴 鼠标模型。第三，我们将获得概念验证数据来激活利用工程设计的信号轴 含有 ApoA1 和 ApoM 的设计师 HDL 颗粒可刺激中性粒细胞分辨率反应 增强血管内皮的存活和再生。这些数据预计将揭示新的 解决过程的机制并启用创新的治疗策略来控制慢性病 炎症性疾病。