IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (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 enhanced when IL-21 signaling was blocked, both in Il21r 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. RNA-Seq analysis using total RNA either from total lung tissues isolated from mouse or from peripheral blood purified from normal donors or AD-HIES patients.

耐甲氧西林金黄色葡萄球菌（Methicillin-resistant Staphylococcus aureus, MRSA）是医院及社区获得性感染的主要病原菌，但宿主抗MRSA的免疫防御机制仍未得到充分阐明。本研究探究了白细胞介素21（Interleukin-21, IL-21）在该过程中的作用。向野生型小鼠气管内给予IL-21后，可诱导颗粒酶表达并增强肺部MRSA的清除能力；但若中性粒细胞被耗竭或加入颗粒酶B抑制剂，该效应则完全消失。相应地，IL-21可诱导人外周血中性粒细胞杀伤MRSA。然而，令人意外的是，在IL-21受体敲除（Il21r KO）小鼠，以及注射IL-21受体-Fc融合蛋白的野生型小鼠中，基础状态下的MRSA清除能力反而得到提升。该现象与I型干扰素（type I interferon）水平升高及干扰素相关基因特征（IFN-related gene signature）上调密切相关，且抗IFNAR1治疗可削弱这些动物体内的MRSA清除效果。此外，本研究发现干扰素β（IFNβ）可通过颗粒酶B依赖的方式诱导颗粒酶B表达并促进MRSA清除。上述结果揭示了IL-21与I型干扰素在抗MRSA先天免疫应答中的相互调控关系。本研究采用RNA测序（RNA-Seq）技术，对小鼠全肺组织提取的总RNA，以及健康供者或常染色体显性高IgE综合征（Autosomal Dominant Hyper-IgE Syndrome, AD-HIES）患者外周血纯化样本的总RNA进行了分析。