近日，来自美国艾尔伯特爱因斯坦医学院的研究人员在著名国际学术期刊nature上发表了一项最新研究进展，他们利用小鼠模型发现体内中性粒细胞衰老与其促炎症活性具有正相关关系，并且中性粒细胞衰老会受到微生物的驱动。
血液中的分叶核中性粒细胞为机体对抗病原体提供了重要的免疫防护作用，但同时也会促进炎症性疾病中的组织损伤。虽然普遍认为中性粒细胞是一个相对同质性的细胞群体，但是也有研究证据表明在中性粒细胞群体中也存在异质性。
在稳定状态下，中性粒细胞的异质性可能来自于细胞衰老也可能来自与骨髓释放的新生中性粒细胞。之前研究证实衰老的中性粒细胞会上调一种帮助清除骨髓内衰老中性粒细胞的受体CXCR4，并产生抑制中性粒细胞产生的反馈抑制，同时对造血干细胞也有一定调控。除此之外，衰老的中性粒细胞亚群还会表达低水平的L-selecin，之前研究已经证明体外培养的衰老中性粒细胞表现出迁移损伤以及促炎症能力下降等特征。
在这项研究中，研究人员在小鼠体内进行了体内衰老分析，发现中性粒细胞的促炎症活性与其在循环中的衰老过程呈现正相关关系。衰老的中性粒细胞代表了一个活跃的细胞亚群，它们表现出增强的αMβ2整合素激活和炎症情况下细胞外诱捕网形成的特征。
研究人员通过深入研究发现微生物可以通过Toll样受体和MyD88介导的信号途径诱导中性粒细胞衰老，清除微生物能够显著减少循环系统中衰老的中性粒细胞数量，并能够改善镰状细胞疾病和内毒素致感染性休克小鼠模型发病及炎症相关的器官损伤。
总的来说，这项研究发现了微生物与促疾病中性粒细胞亚群之间的调控关系，证明了微生物可以驱动中性粒细胞衰老，加重炎症反应，这为中性粒细胞相关的炎症性疾病治疗提供了重要信息。
Neutrophil ageing is regulated by the microbiome
Dachuan Zhang,Grace Chen,Deepa Manwani,Arthur Mortha,Chunliang Xu,Jeremiah J. Faith,Robert D. Burk,Yuya Kunisaki,Jung-Eun Jang,Christoph Scheiermann,Miriam Merad & Paul S. Frenette
Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases1, 2. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging3, 4. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow5. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow6, 7, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis8, and rhythmic modulation of the haematopoietic stem-cell niche5. The aged subset also expresses low levels of L-selectin5, 9. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties6, 10. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.