Modulation of erythrocyte function by complement

补体对红细胞功能的调节

• 批准号: 8631096
• 负责人: IONITA Calin GHIRAN
• 金额: $ 42.63万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631096
• 关键词: Address; Adherence; Antigen-Antibody Complex; Attenuated; Autocrine Communication; Autoimmune Diseases; Binding; Biochemical; Blood; Blood Circulation; Blood capillaries; Cell membrane; Cell physiology; Cells; Cellular biology; Cessation of life; Complement; Complement 3b; Complement 4b; Complement Activation; Complement Receptor; Data; Deposition; Development; Distress; Endothelial Cells; Environment; Erythrocytes; Event; Excision; Feedback; Gases; Generations; Glycophorin A; Goals; Homeostasis; Human; Image; Immune; Immune response; In Vitro; Infection; Inflammatory; Injury; Intercept; Ligation; Liver; Malaria; Mediating; Membrane; Microbe; Microcirculation; Microscopy; Morbidity - disease rate; Organ; Oxygen; Pathology; Patients; Perfusion; Phenotype; Physiological; Primates; Purinoceptor; Role; Sepsis; Septic Shock; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Spleen; System; Therapeutic; Tissues; Trauma; Video Microscopy; Work; autocrine; base; capillary; clinically relevant; cost; density; design; effective therapy; immune clearance; improved; in vivo; in vivo imaging; innovation; macrophage; mortality; multiorgan injury; neutrophil; novel; novel therapeutics; paracrine; particle; prevent; public health relevance; response; septic; therapeutic target

DESCRIPTION (provided by applicant): Excessive complement activation is associated with a wide spectrum of pathologies including malaria, sickle cell disease, autoimmune diseases, trauma injury, and sepsis. In the U.S., sepsis alone is responsible for over 210,000 deaths each year, with associated costs estimated at over $16.7 billion. Our current understanding of sepsis is that complement-mediated host immune responses to infection are responsible for microcirculatory distress and severe organ damage. Red blood cells (RBCs) have critical, non- redundant roles in maintaining a non-inflammatory intravascular environment by capturing complement- opsonized particles through complement receptor 1 (CR1) and delivering them to macrophages in the liver and spleen. We have found that during excessive complement activation the additional engagement of glycophorin A (GPA) by soluble complement fragments significantly inhibits RBC membrane deformability and promotes RBC ATP release. Our new data challenge the classic paradigm of RBCs as singularly non-inflammatory cells, revealing that during excessive complement activation, RBCs cease to maintain a non-inflammatory environment and actively promote a pro-inflammatory intravascular milieu. Mechanisms responsible for changing RBCs into proinflammatory cells have not been known. A better understanding of the "reprogramming" of RBCs into proinflammatory cells will allow the development of novel, effective therapies for septic patients. The long-term objective of this work is to understand the contribution of RBCs and complement to tissue and organ damage during sepsis. Our overall hypothesis is that during excessive complement activation, engagement of GPA by excess complement fragments reprograms RBCs into pro- inflammatory cells through a critical ATP-dependent autocrine signaling mechanism. The overall objective of our proposal is to determine the mechanisms by which engagement of GPA by complement fragments promote ATP release and inhibit RBC functions. The rational for these studies is that we have revealed a unique and crucial purinergic requirement for the GPA-mediated detrimental effect of complement on RBC functions, which suggests that RBC-generated ATP, through autocrine and paracrine purinergic mechanisms, promotes and maintains an inflammatory intravascular milieu. The innovation of our studies is that we have discovered a novel facet of RBC-complement interaction that may considerably impact the efficacy and design of targeted therapeutic approaches that will significantly lower the morbidity and mortality of sepsis. Our studies will have a significant impact on our understanding of the potential of RBCs and purinergic signaling as novel targets for therapy in pathological situation associated with excessive complement activation, as well as on our basic understanding of RBC biology in normal and pathological situations.

描述（由申请人提供）：过度补体激活与包括疟疾，镰状细胞疾病，自身免疫性疾病，创伤损伤和败血症在内的多种病理有关。在美国，仅败血症就会每年造成21万多人死亡，相关费用估计超过167亿美元。我们目前对败血症的理解是，补体介导的宿主对感染的免疫反应是微循环遇险和严重器官损伤的原因。红细胞（RBC）通过补体受体1（CR1）捕获补体的互补颗粒，并将其输送到肝脏和脾脏中的巨噬细胞中，在维持非炎性的血管内环境中具有关键的，非冗余的作用。我们发现，在过度补体​​激活期间，可溶性补体片段通过可溶性补体片段的额外参与会显着抑制RBC膜变形性，并促进RBC ATP释放。我们的新数据挑战了RBC的经典范式作为奇异的非炎性细胞，表明在过度补体​​激活期间，RBC不再保持非炎症环境，并积极促进促炎性炎症性血管内部环境。尚不知道负责将RBC变成促炎细胞的机制。更好地了解RBC在促炎细胞中的“重编程”将允许为化粪池患者开发新的有效疗法。这项工作的长期目标是了解RBC的贡献并补充败血症期间的组织和器官损伤。我们的总体假设是，在过度补体​​激活期间，通过过量补体片段通过关键的ATP依赖性自分泌信号传导机制将RBC重新编程重新编程将RBC重新编程为炎性细胞。我们建议的总体目的是确定通过补体片段促进ATP释放并抑制RBC功能的GPA参与的机制。这些研究的理性是，我们揭示了补体对RBC功能的GPA介导的有害作用的独特而关键的嘌呤能需求，这表明RBC生成的ATP通过自动分泌和旁分泌和旁分泌嘌呤能机制，促进和维持炎症性内血管内的内膜。我们的研究的创新是，我们发现了RBC弥补相互作用的新方面，可能会大大影响有针对性的治疗方法的功效和设计，这将大大降低败血症的发病率和死亡率。我们的研究将对我们对RBC的潜力和嘌呤能信号传导的理解产生重大影响，这是与过度补体激活相关的病理状况中治疗的新靶标，以及我们对正常和病理情况下RBC生物学的基本理解。

项目成果

Ligation of Glycophorin A Generates Reactive Oxygen Species Leading to Decreased Red Blood Cell Function.

• DOI: 10.1371/journal.pone.0141206
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Khoory J;Estanislau J;Elkhal A;Lazaar A;Melhorn MI;Brodsky A;Illigens B;Hamachi I;Kurishita Y;Ivanov AR;Shevkoplyas S;Shapiro NI;Ghiran IC
• 通讯作者: Ghiran IC

CR1-mediated ATP Release by Human Red Blood Cells Promotes CR1 Clustering and Modulates the Immune Transfer Process

• DOI: 10.1074/jbc.m113.486035
• 发表时间: 2013-10-25
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Melhorn, Mark I.;Brodsky, Abigail S.;Ghiran, Ionita C.
• 通讯作者: Ghiran, Ionita C.