Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208 USA.
Department of Biochemistry, University of Science, Vietnam National University, Ward 4, District 5, Ho Chi Minh City 749000, Vietnam.
Nat Commun. 2017 Jun 5;8:15564. doi: 10.1038/ncomms15564.
Pyrin domain-only proteins (POPs) are recently evolved, primate-specific proteins demonstrated in vitro as negative regulators of inflammatory responses. However, their in vivo function is not understood. Of the four known POPs, only POP2 is reported to regulate NF-κB-dependent transcription and multiple inflammasomes. Here we use a transgenic mouse-expressing POP2 controlled by its endogenous human promotor to study the immunological functions of POP2. Despite having significantly reduced inflammatory cytokine responses to LPS and bacterial infection, POP2 transgenic mice are more resistant to bacterial infection than wild-type mice. In a pulmonary tularaemia model, POP2 enhances IFN-γ production, modulates neutrophil numbers, improves macrophage functions, increases bacterial control and diminishes lung pathology. Thus, unlike other POPs thought to diminish innate protection, POP2 reduces detrimental inflammation while preserving and enhancing protective immunity. Our findings suggest that POP2 acts as a high-order regulator balancing cellular function and inflammation with broad implications for inflammation-associated diseases and therapeutic intervention.
吡啶结构域仅有的蛋白质（POPs）是最近进化而来的，灵长类动物特有的蛋白质，在体外被证明是炎症反应的负调节剂。然而，它们的体内功能尚不清楚。在已知的四种 POPs 中，只有 POP2 被报道可调节 NF-κB 依赖性转录和多种炎性体。在这里，我们使用一种由其内源人启动子控制的表达 POP2 的转基因小鼠来研究 POP2 的免疫学功能。尽管 POP2 转基因小鼠对 LPS 和细菌感染的炎症细胞因子反应显著降低，但它们比野生型小鼠更能抵抗细菌感染。在肺土拉菌病模型中，POP2 增强了 IFN-γ 的产生，调节了中性粒细胞的数量，改善了巨噬细胞的功能，增加了细菌的控制并减少了肺部病变。因此，与其他被认为降低先天保护的 POPs 不同，POP2 减少了有害炎症，同时保留和增强了保护性免疫。我们的发现表明，POP2 作为一种高级调节剂，平衡细胞功能和炎症，对炎症相关疾病和治疗干预具有广泛的意义。
