Macrophage Functional Response in Hemolytic Complications

溶血并发症中的巨噬细胞功能反应

• 批准号: 10023593
• 负责人: Francesca Vinchi
• 金额: $ 49.05万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10023593
• 关键词: Acute; Address; Adoptive Transfer; Alveolar; Anti-Inflammatory Agents; Antiinflammatory Effect; Autophagocytosis; Babesia; Babesiosis; Blood Circulation; Blood Vessels; Bone Marrow; Cells; Chronic; Data; Development; Disease; Disease model; Embolism; Equilibrium; Erythrocyte Transfusion; Erythrocytes; Erythrophagocytosis; Event; Exposure to; Fatty acid glycerol esters; Functional disorder; Goals; HIF1A gene; Heme; Hemolysis; Hepatic; Infection; Inflammation; Inflammatory; Inflammatory Response; Iron; Island; Light; Lipids; Liver Fibrosis; Lung; Lung Inflammation; Lung infections; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; NF-kappa B; NFKB Signaling Pathway; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phagocytosis; Phenotype; Plasma; Population; Prevention; Property; Publishing; Quinine; Role; Sickle Cell Anemia; Signal Transduction; Sputum; Stimulus; Symptoms; Syndrome; TRAF6 gene; Testing; Thalassemia; Therapeutic; Tissues; Transfusion; Vascular Endothelium; Vesicle; acute chest syndrome; base; beta Thalassemia; cytokine; improved; inhibitor/antagonist; insight; interstitial; lung injury; macrophage; metabolome; mortality; mouse model; new therapeutic target; novel therapeutics; premature; prevent; response; response to injury; stressor; synergism; translational study

ABSTRACT Hemolytic diseases, including sickle cell disease (SCD) and β-thalassemia (THAL), are generally hallmarked by hemolysis and chronic inflammation. The mechanism underlying the different extent of inflammation in these diseases is unknown (SCD>THAL). Our published findings revealed that, besides promoting vascular endothelium activation, free heme triggers a M1-like pro-inflammatory phenotypic switching of reticulo- endothelial macrophages which alters their functional properties. Recently, we observed that the exposure to intact red blood cells (RBCs), and therefore erythrophagocytosis, induces a M2-like anti-inflammatory macrophage phenotype. This led us to hypothesize that the differential degree of inflammation between SCD and THAL is determined by the type of hemolysis, either intra-vascular (SCD) or extra-vascular (THAL), with different effects on macrophage functions. In Aim 1 we will address the concept that whereas in SCD inflammation is triggered by heme-induced M1-like macrophages, in THAL it is in part ‘blunted’ by erythrophagocytosis-induced M2-like macrophages. We believe that this mechanism similarly underlies the anti-inflammatory effect of fresh RBC transfusions and the detrimental effect of old RBC transfusions in SCD through the exposure of macrophages to heme in intact RBCs or in free form, respectively. To test this hypothesis we will take advantage of mouse models of intra- and extra-vascular hemolysis and compare SCD and THAL mice, as well as analyze another hemolytic condition, Babesia infection, and study the differential phenotypic switching of tissue macrophages induced by these events on macrophage activation and inflammation. Finally, we will interrogate cell metabolome, with the hypothesis that free heme promotes M1 polarization via TRAF6/NF-kB and/or Akt/mTORC1/HIF1α-triggered glycolytic switching. We further posit that this mechanism has relevance for acute chest syndrome (ACS), a main cause of morbidity and mortality in SCD. In Aim 2 we will address the central hypothesis that by mediating lung macrophage inflammatory phenotypic switching, heme promotes ACS and exacerbates symptoms in response to infections and fat emboli. To address this, we plan to assess the contribution of heme-induced M1 macrophages to ACS pathophysiology in SCD mice and validate the findings in SCD patients under steady-state and ACS condition by analyzing sputum macrophage polarization/function with plasma/sputum heme and cytokines levels and studying the functional alterations induced by free heme exposure in sputum macrophages of steady-state SCD patients. Finally, we will test whether transfusions, metabolic modulators and adoptive transfer of macrophages with increased iron export ability and anti-inflammatory/anti-hemolytic therapies can mitigate ACS, by triggering or reprogramming macrophages towards an anti-inflammatory phenotype. Our translational study is expected to (i) shed light on the mode of action of heme as lung stressor in ACS, with a focus on the newly observed heme-activated macrophages; (ii) improve transfusion practice in SCD and THAL and understand its beneficial effect in ACS; (iii) identify new targets and test strategies to implement the current therapeutic options. Our goal is to propose novel targeted therapies for chronic inflammation and ACS based on the modulation of macrophage polarization.

抽象的 溶血性疾病，包括镰状细胞病 (SCD) 和 β-地中海贫血 (THAL)，通常具有明显的特征 溶血和慢性炎症的机制不同程度的炎症。 这些疾病是未知的（SCD>THAL），我们发表的研究结果表明，除了促进血管疾病之外。 内皮细胞激活，游离血红素触发网状细胞的 M1 样促炎表型转换 最近，我们观察到，暴露于内皮巨噬细胞会改变其功能特性。 完整的红细胞 (RBC) 以及因此的红细胞吞噬作用可诱导 M2 样抗炎作用 这导致我们争论 SCD 之间炎症程度的差异。 THAL 由溶血类型决定，是血管内溶血 (SCD) 还是血管外溶血 (THAL)， 在目标 1 中，我们将讨论 SCD 中的概念。 炎症是由血红素诱导的 M1 样巨噬细胞引发的，在 THAL 中，炎症被部分“减弱” 我们认为，这种机制同样是吞噬红细胞作用诱导的 M2 样巨噬细胞的基础。 新鲜红细胞输注的抗炎作用和旧红细胞输注对 SCD 的不利影响 通过将巨噬细胞分别暴露于完整红细胞或游离形式的血红素来测试这一点。 假设我们将利用血管内和血管外溶血的小鼠模型来比较 SCD 和 THAL 小鼠，并分析另一种溶血情况，巴贝虫感染，并研究差异 这些事件诱导的组织巨噬细胞表型转换对巨噬细胞活化和 最后，我们将探究细胞代谢组，假设游离血红素促进 M1。 通过 TRAF6/NF-kB 和/或 Akt/mTORC1/HIF1α 触发的糖酵解转换进行极化。 这种机制与急性胸部综合征（ACS）有关，急性胸部综合征是导致患者发病和死亡的主要原因。 在目标 2 中，我们将讨论通过介导肺巨噬细胞炎症的中心假设。 表型转换、血红素促进 ACS 并使感染和脂肪引起的症状恶化 为了解决这个问题，我们计划评估血红素诱导的 M1 巨噬细胞对 ACS 的贡献。 SCD 小鼠的病理生理学并验证稳态和 ACS 条件下 SCD 患者的研究结果 通过血浆/痰血红素和细胞因子水平分析痰巨噬细胞极化/功能， 研究稳态痰巨噬细胞中游离血红素暴露引起的功能改变 最后，我们将测试是否输血、代谢调节剂和过继转移。 具有增强的铁输出能力的巨噬细胞和抗炎/抗溶血疗法可以减轻 ACS，通过触发或重新编程巨噬细胞达到抗炎表型。 研究预计将 (i) 阐明血红素作为 ACS 肺应激源的作用模式，重点是 (ii) 改进 SCD 和 THAL 的输血实践， (iii) 确定新的目标和测试策略以实施当前的目标 我们的目标是提出针对慢性炎症和 ACS 的新型靶向疗法。 巨噬细胞极化的调节。