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.

宿主免疫系统失调会削弱心脏功能，从而大大增加了患病的几率脓毒症导致重症患者死亡。尽管经过数十年的深入研究，基本机制仍然存在难以捉摸。特别是尸检结果表明，大多数脓毒症患者都有未解决的感染灶，这表明巨噬细胞功能受损无法根除入侵的病原体。因此，任何增强巨噬细胞功能的策略有望提高患者的总体生存率。我们最近做出了新的发现，分泌和跨膜 1 (Sectm1) 的水平，一种通常高度在髓系免疫细胞和上皮细胞中表达，在脓毒症患者血液中显着降低患者与健康捐献者相比。一致的是，我们的最新数据还表明 Sectm1a 的表达水平，人类 Sectm1 的小鼠同源物，在外周血单核细胞和腹膜中大大减少与对照小鼠相比，从脓毒症小鼠中收集的巨噬细胞。因此，Sectm1a-敲除（KO）小鼠表现出：1）血液和腹腔灌洗液中的细菌载量较高，2）全身性增加炎症反应，3) 与相比，心脏功能恶化以及存活率较低败血症条件下的野生型（WT）小鼠。从机制上讲，Sectm1a-KO 巨噬细胞表现出吞噬作用和杀灭细菌的能力受损。相比之下，Sectm1a 的强制表达巨噬细胞增强吞噬能力和杀菌活性。因此，测试很重要巨噬细胞特异性过度表达 Sectm1a 是否可以通过增强免疫功能来预防脓毒症细菌清除。我们的试验数据还表明巨噬细胞 Sectm1a 可以引发自分泌作用通过与 TNFRSF18 的膜受体（TNF 受体超家族膜 18，也称为 GITR 或 CD357，以下简称 GITR）。后续实验表明，巨噬细胞的治疗重组 Sectm1a 蛋白激活 GITR 信号传导，从而增强吞噬能力。因此，测试将重组 Sectm1a 蛋白注射到脓毒症小鼠中是否不仅可以促进细菌清除，还可以降低全身炎症反应，改善心肌功能以及动物的生存。这些转化想法将通过追求三个具体目标进行测试：1）定义使用巨噬细胞特异性方法研究 Sectm1a 在多种微生物败血症期间巨噬细胞中的确切作用 Sectm1a过表达小鼠模型； 2) 确定 Sectm1a 引发反作用的机制脓毒症依赖于 GITR，使用 GITR 敲除小鼠模型； 3) 研究治疗方法使用重组 Sectm1a 蛋白治疗脓毒症的潜力。拟议的研究预计将确定 Sectm1a 是一种有效的新型宿主免疫调节剂，也是预防脓毒症的主要保护剂。如果经过验证，该提案的研究结果应该为增强巨噬细胞提供新的治疗选择在脓毒症期间发挥清除细菌的作用，并有望最大限度地减少脓毒症引起的死亡。