Roles of Sectm1a in macrophages and cardiac function during sepsis

脓毒症期间 Sectm1a 在巨噬细胞和心脏功能中的作用

基本信息

批准号：
9898412
负责人：
Guo-Chang Fan
金额：
$ 28.44万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898412
关键词：
Address Adoptive Transfer Affect Agonist Animals Antibiotic Therapy Antisepsis Attenuated Autopsy Bacteremia Bacteria Bacterial Infections Binding Biochemical Biology Blood CD7 gene Cardiomyopathies Cardiovascular system Cause of Death Cells Cessation of life Critical Care Critical Illness Data Epithelial Cells Exhibits Failure Functional disorder Harvest Heart Injuries Homologous Gene Host Defense Human Immune Immune System Diseases Immune system Immunity Immunologics Impairment Inflammation Inflammatory Response Injections Innate Immune Response Intensive Care Invaded Knock-out Knockout Mice Knowledge Lead Ligands Link Liquid substance Measures Mediating Mediator of activation protein Membrane Mission Modality Monitor Mus Myelogenous Myocardial Operative Surgical Procedures Partner in relationship Pathogenesis Patients Peritoneal Fluid Peritoneal Macrophages Peritoneal lavage Phagocytes Phagocytosis Physiological Play Process Proteins Public Health Recombinants Regulation Research Role SECTM1 gene Sepsis Signal Transduction Surface Survival Rate T-Lymphocyte Testing Therapeutic Time Transgenic Mice Transgenic Organisms Translating Tumor Necrosis Factor Receptor United States National Institutes of Health Wild Type Mouse Work animal mortality autocrine bactericide cecal ligation puncture disability experimental study follow-up heart function human disease impaired capacity improved in vivo knock-down macrophage member monocyte mortality mouse model novel novel strategies novel therapeutics overexpression pathogen peripheral blood polymicrobial sepsis pre-clinical promoter protective effect receptor septic septic patients systemic inflammatory response tool translational study

项目摘要

Dysregulation of the host immune system that weakens cardiac function greatly increases the odds of sepsis-induced death in critically ill patients. Despite decades of intensive study, basic mechanisms remain elusive. In particular, autopsy results indicate that most patients with sepsis had unresolved infectious foci, suggesting that impaired macrophage function fails to eradicate the invading pathogens. Therefore, any strategies that boost macrophage function would be expected to improve overall patient survival. We recently made the novel findings that the levels of secreted and transmembrane 1 (Sectm1), a protein normally highly expressed in immune cells of myeloid lineage and epithelial cells, was significantly lower in the blood of septic patients than healthy donors. Consistently, our latest data also showed that the expression levels of Sectm1a, a mouse homolog of human Sectm1, were greatly reduced in peripheral blood monocytes and peritoneal macrophages collected from septic mice, compared to control mice. Accordingly, Sectm1a-knockout (KO) mice exhibited: 1) a higher bacterial load in the blood and peritoneal lavage fluid, 2) an increased systemic inflammatory response, and 3) a deteriorated cardiac function as well as a lower survival rate, compared to wild-type (WT) mice under sepsis conditions. Mechanistically, Sectm1a-KO macrophages showed the impaired capacity of phagocytosis and bacterial killing. By contrast, forced expression of Sectm1a in macrophages augmented phagocytic capacity and bactericidal activity. Hence, it will be important to test whether macrophage-specific overexpression of Sectm1a can protect against sepsis through enhancing bacterial clearance. Our pilot data have also revealed that macrophage Sectm1a can elicit autocrine action by binding strongly to the membrane receptor of TNFRSF18 (TNF receptor superfamily membrane 18, also known as GITR or CD357, hereafter GITR). Follow-up experiments showed that treatment of macrophages with recombinant Sectm1a protein activated GITR signaling, which in turn enhanced phagocytic capacity. Thus, it will be important to test if injection of recombinant Sectm1a protein into septic mice not only promotes bacterial clearance, but also reduces the systemic inflammatory response, and improves myocardial function as well as animal survival. These translational ideas will be tested by pursuing three specific aims: 1) Define the exact role of Sectm1a in macrophages during polymicrobial sepsis, using a macrophage-specific Sectm1a-overexpressing mouse model; 2) Identify the mechanism by which Sectm1a-elicited anti- sepsis is dependent on GITR, using a GITR-knockout mouse model; and 3) Investigate the therapeutic potential using recombinant Sectm1a protein to treat sepsis. The proposed studies are expected to identify Sectm1a as a potent and novel regulator of host immunity and a major protector against sepsis. If verified, the findings from this proposal should provide new therapeutic options for boosting macrophage function in the clearance of bacteria during sepsis and hopefully, to minimize sepsis-induced death.

降低心脏功能的宿主免疫系统的失调大大增加了几率重症患者败血症引起的死亡。尽管进行了数十年的深入研究，但仍然存在基本机制难以捉摸。特别是，尸检结果表明，大多数败血症患者的感染灶尚未解决，表明巨噬细胞功能受损的功能无法消除入侵的病原体。因此，任何人提高巨噬细胞功能的策略将有望改善总体患者生存率。我们最近提出了新的发现，即分泌和跨膜1（sectm1）的水平，一种通常高度的蛋白在化粪池的血液中，在髓样谱系和上皮细胞的免疫细胞中表达明显降低患者比健康的捐助者。一致地，我们的最新数据还表明sectm1a的表达水平，人类宗派的小鼠同源物在外周血单核细胞和腹膜中大大降低与对照小鼠相比，从化粪池小鼠收集的巨噬细胞。因此，Sectm1a-Knockout（KO）显示的小鼠：1）血液和腹膜灌洗液中的细菌负荷较高，2）全身增加炎症反应和3）与心脏功能恶化以及较低的存活率相比败血症条件下的野生型（WT）小鼠。从机械上讲，sectm1a-ko巨噬细胞显示吞噬作用和细菌杀伤的能力受损。相比之下，在巨噬细胞增强了吞噬能力和杀菌活性。因此，测试很重要 sectm1a的巨噬细胞特异性过表达是否可以通过增强来预防败血症细菌清除率。我们的试点数据还显示，巨噬细胞宗派可以引起自分泌作用通过与TNFRSF18的膜受体强烈结合（TNF受体超家族膜18，也称为Gitr或CD357，以下称为Gitr）。后续实验表明巨噬细胞的治疗重组Sectm1a蛋白激活的GITR信号传导，进而增强了吞噬能力。因此，测试重组宗派蛋白是否在化粪池小鼠中注射是否会促进细菌清除率，但也降低了全身性炎症反应，并改善心肌功能以及动物的生存。这些翻译思想将通过追求三个具体目标来测试：1）定义使用巨噬细胞特异性过表达sectm1a的鼠标模型； 2）确定sectm1a引诱的抗 - 的机制败血症使用gitr-knockout鼠标模型依赖于gitr。 3）研究治疗使用重组Sectm1a蛋白治疗败血症的潜力。拟议的研究预计将将Sectm1a识别为宿主免疫的有效和新型调节剂，并且是针对败血症的主要保护者。如果经过验证，该提案的发现应为增强巨噬细胞提供新的治疗选择在败血症期间的细菌清除和希望最小化败血症诱导的死亡中的作用。