Fallon Eleanor A, Chun Tristen T, Young Whitney A, Gray Chyna, Ayala Alfred, Heffernan Daithi S
Division of Surgical Research, Department of Surgery, Brown University and Rhode Island Hospital, Providence, RI, United States.
Front Immunol. 2017 Nov 20;8:1469. doi: 10.3389/fimmu.2017.01469. eCollection 2017.
We have shown that invariant natural killer T (NKT) cells mediate sepsis-induced end-organ changes and immune responses, including macrophage bacterial phagocytosis, a finding regulated by the check point protein program cell death receptor-1 (PD-1). Furthermore, PD-1 mediates mortality in both adult and neonatal murine sepsis as well as in surgical patients. Given our previous findings, we hypothesize that NKT cells will also modulate neonatal sepsis survival, and that this effect is regulated in part through PD-1. We utilized a polymicrobial intra-peritoneal cecal slurry (CS) sepsis model in wild type (WT), NKT or PD-1 5-7 day old neonatal pups. Typically, tissues were harvested at 24 h for various bioassays/histology and, in some cases, survival was assessed for up to 7 days. Interestingly, similar to what we recently reported for PD-1 mice following CS, NKT-deficient animals exhibit a markedly improved survival vs. WT. Histologically, minor alterations in liver architectural, which were noted in WT pups, were attenuated in both NKT and PD-1 pups. Following CS, PECAM-1 expression was unchanged in the WT pups but increased in both NKT and PD-1 pups. In WT, following CS the emergence of a Ly6C subpopulation was noted among the influxed peritoneal macrophage population. Conversely, within NKT pups, there were fewer peritoneal macrophages and a greater percentage of Ly6C macrophages. We show not only a key role for NKT cells in affecting end-organ damage as well as alterations in phagocytes phenotypes in neonatal sepsis but that this NKT cell mediated effect is driven by the central checkpoint protein PD-1.
我们已经表明，不变自然杀伤T（NKT）细胞介导脓毒症诱导的终末器官变化和免疫反应，包括巨噬细胞的细菌吞噬作用，这一发现受检查点蛋白程序性细胞死亡受体-1（PD-1）调控。此外，PD-1介导成年和新生小鼠脓毒症以及外科患者的死亡率。鉴于我们之前的研究结果，我们推测NKT细胞也会调节新生小鼠脓毒症的存活率，并且这种作用部分是通过PD-1调节的。我们在野生型（WT）、NKT或PD-1基因敲除的5至7日龄新生幼鼠中使用了多微生物腹腔盲肠灌洗液（CS）脓毒症模型。通常，在24小时时采集组织用于各种生物测定/组织学检查，在某些情况下，评估长达7天的存活率。有趣的是，与我们最近报道的CS处理后的PD-1基因敲除小鼠相似，NKT细胞缺陷的动物与WT相比存活率显著提高。组织学上，WT幼鼠肝脏结构的轻微改变在NKT和PD-1基因敲除幼鼠中均减轻。CS处理后，WT幼鼠中血小板内皮细胞黏附分子-1（PECAM-1）的表达未改变，但在NKT和PD-1基因敲除幼鼠中均增加。在WT中，CS处理后，在流入的腹腔巨噬细胞群体中发现了Ly6C亚群的出现。相反，在NKT基因敲除幼鼠中，腹腔巨噬细胞较少，Ly6C巨噬细胞的比例较高。我们不仅表明NKT细胞在影响新生小鼠脓毒症的终末器官损伤以及吞噬细胞表型改变中起关键作用，而且这种NKT细胞介导的作用是由中心检查点蛋白PD-1驱动的。
