Myeloid sphingolipid regulation of tissue resolution and regeneration responses

摘要 先天免疫系统的髓样细胞(中性粒细胞和巨噬细胞)与 血管内皮细胞调节炎症反应和消退反应。在早期阶段， 炎症反应，不适当的中性粒细胞激活会导致血管和实质损伤。 然而，在炎症的晚期，精确控制的中性粒细胞分解机制现在是 被认为对限制组织损伤和启动新的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的早期阶段功能良好 理解，它们参与解决反应知之甚少。我们发现， 鞘氨醇1-磷酸(S1P)受体-1(S1PR1)，一种G蛋白偶联受体(GPCR)，与 血管和获得性免疫(T和B)细胞的成熟功能，调节中性粒细胞的分解 回应。具体地说，S1PR1信号诱导了一种非炎性、长寿的中性粒细胞表型， 进行有效的吞噬作用。我们还发现，中性粒细胞的这一新的和未被认识的功能 S1PR1信号轴对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 肝功能衰竭。为了激活这一有益的过程，我们基于我们对S1P的了解开发了一种新的生物 监护人。我们假设中性粒细胞中的局部S1PR1信号是一种通用的机制，可以解决 炎症组织损伤，从而使血管和实质在多个器官系统中再生。 此外，我们假设，这个信号轴的治疗性激活可能提供了一种新的策略来控制 慢性阴燃炎症，导致纤维化疾病和器官功能障碍。为了检验这一假设， 我们将研究受S1PR1调控的GPCR近端机制和核转录事件 在组织中性粒细胞分解反应过程中。第二，我们将研究这一信号的重要性 AXIS在病毒诱导的肺损伤和化学诱导的肝损伤后诱导的分解反应中的作用 老鼠模型。第三，我们将获得概念验证数据来激活该信令轴，该信令轴利用 含有载脂蛋白A1和载脂蛋白的设计高密度脂蛋白颗粒，可刺激中性粒细胞分解反应和 促进血管内皮细胞存活和再生。这些数据预计将揭示出新颖的 解决过程的机制并使创新的治疗策略能够控制慢性 炎症性疾病。

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.