Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States.
Elife. 2019 Apr 16;8:e45501. doi: 10.7554/eLife.45501.
Methicillin-resistant (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNβ induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRSA.
耐甲氧西林金黄色葡萄球菌（MRSA）是一种主要的医院和社区获得性病原体，但宿主对 MRSA 的防御机制仍知之甚少。在这里，我们研究了白细胞介素 21（IL-21）在这个过程中的作用。当将其气管内给药到野生型小鼠中时，IL-21 诱导了颗粒酶并增强了肺部 MRSA 的清除，但当耗尽中性粒细胞或添加颗粒酶 B 抑制剂时则不会。相应地，IL-21 诱导人外周血中性粒细胞杀死 MRSA。然而出乎意料的是，当阻断 IL-21 信号转导时，无论是在 KO 小鼠还是在注射 IL-21R-Fc 融合蛋白的野生型小鼠中，基础 MRSA 的清除也得到了增强。这与 I 型干扰素的增加和与 IFN 相关的基因特征相关，事实上，抗 IFNAR1 治疗会减少这些动物中 MRSA 的清除。此外，我们发现 IFNβ 以颗粒酶 B 依赖性的方式诱导颗粒酶 B 并促进 MRSA 的清除。这些结果揭示了 IL-21 和 I 型 IFN 在针对 MRSA 的先天免疫反应中的相互作用。
