Roles of Sectm1a in macrophages and cardiac function during sepsis

宿主免疫系统的失调会削弱心脏功能，这大大增加了心脏病的几率。 脓毒症导致的重症患者死亡。尽管经过了几十年的深入研究， 难以捉摸。特别是，尸检结果表明，大多数脓毒症患者有未解决的感染灶， 表明受损的巨噬细胞功能不能根除入侵的病原体。因此任何 增强巨噬细胞功能的策略有望改善患者的总体存活率。我们最近 新的发现是分泌和跨膜1（Sectm 1），一种通常高度表达的蛋白质， 在骨髓系免疫细胞和上皮细胞中表达，在脓毒症患者血液中的表达显著降低， 病人比健康的捐赠者。同样，我们最新的数据也表明Sectm 1a， 人Sectm 1的小鼠同源物，在外周血单核细胞和腹膜炎中显著降低， 与对照小鼠相比，从脓毒症小鼠收集的巨噬细胞。因此，Sectm 1a敲除（KO） 小鼠表现出：1）血液和腹膜灌洗液中较高的细菌负荷，2）增加的全身性 炎症反应，和3）恶化的心脏功能以及较低的存活率，相比之下， 在败血症条件下的野生型（WT）小鼠。机制上，Sectm 1a-KO巨噬细胞显示， 吞噬和杀菌能力受损。相比之下，Sectm 1a在 巨噬细胞增强吞噬能力和杀菌活性。因此，测试 巨噬细胞特异性Sectm 1a过表达是否可以通过增强 细菌清除率我们的初步数据还显示，巨噬细胞Sectm 1a可以引起自分泌作用， 通过与TNFRSF 18的膜受体（TNF受体超家族膜18，也 称为GITR或CD 357，下文称为GITR）。后续实验表明，治疗巨噬细胞 重组Sectm 1a蛋白激活GITR信号，这反过来又增强了吞噬能力。 因此，重要的是测试将重组Sectm 1a蛋白注射到脓毒症小鼠中是否不仅促进 细菌清除，而且还减少全身炎症反应，并改善心肌功能 以及动物的生存。这些翻译的想法将通过追求三个具体目标进行测试：1）定义 Sectm 1a在多微生物脓毒症中巨噬细胞中的确切作用，使用巨噬细胞特异性 Sectm 1a-过表达小鼠模型; 2）鉴定Sectm 1a-引起抗- 败血症依赖于GITR，使用GITR敲除小鼠模型;和3）研究治疗性GITR依赖于GITR。 利用重组Sectm 1a蛋白治疗败血症的潜力。预计拟议的研究将 确定Sectm 1a是一种有效和新的宿主免疫调节剂，也是对抗脓毒症的主要保护剂。如果 经过验证，这项建议的发现应该为增加巨噬细胞提供新的治疗选择。 在脓毒症期间清除细菌的功能，并有望使脓毒症诱导的死亡最小化。

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.