Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Eur J Immunol. 2023 May;53(5):e2250339. doi: 10.1002/eji.202250339. Epub 2023 Apr 24.
Polyphosphates are highly conserved, linear polymers of monophosphates that reside in all living cells. Bacteria produce long chains containing hundreds to thousands of phosphate units, which can interfere with host defense to infection. Here, we report that intratracheal long-chain polyphosphate administration to C57BL/6J mice resulted in the release of proinflammatory cytokines and influx of Ly6G polymorphonuclear neutrophils in the bronchoalveolar lavage fluid causing a disruption of the physiologic endothelial-epithelial small airway barrier and histologic signs of lung injury. Polyphosphate-induced effects were attenuated after neutrophil depletion in mice. In isolated murine neutrophils, long-chain polyphosphates modulated cytokine release induced by lipopolysaccharides (LPS) from Gram-negative bacteria or lipoteichoic acid from Gram-positive bacteria. In addition, long-chain polyphosphates induced immune evasive effects in human neutrophils. In detail, long-chain polyphosphates downregulated CD11b and curtailed the phagocytosis of Escherichia coli particles by neutrophils. Polyphosphates modulated the migration capacity by inducing CD62L shedding resulting in CD62L and CD11b neutrophils. The release of IL-8 induced by LPS was also significantly reduced. Pharmacologic blockade of PI3K with wortmannin antagonized long-chain polyphosphate-induced effects on LPS-induced IL-8 release. In conclusion, polyphosphates govern immunomodulation in murine and human neutrophils, suggesting polyphosphates as a therapeutic target for bacterial infections to restore innate immune defense.
聚磷酸盐是高度保守的、线性的一磷酸盐聚合物，存在于所有活细胞中。细菌产生含有数百到数千个磷酸盐单元的长链，这可能会干扰宿主对感染的防御。在这里，我们报告说，向 C57BL/6J 小鼠气管内给予长链聚磷酸盐会导致促炎细胞因子的释放和 Ly6G 多形核中性粒细胞涌入支气管肺泡灌洗液，导致生理内皮-上皮小气道屏障的破坏和肺损伤的组织学迹象。在小鼠中性粒细胞耗竭后，聚磷酸盐诱导的作用减弱。在分离的鼠中性粒细胞中，长链聚磷酸盐调节了革兰氏阴性菌脂多糖（LPS）或革兰氏阳性菌脂磷壁酸诱导的细胞因子释放。此外，长链聚磷酸盐在人中性粒细胞中诱导免疫逃避效应。具体而言，长链聚磷酸盐下调 CD11b 并抑制中性粒细胞对大肠杆菌颗粒的吞噬作用。聚磷酸盐通过诱导 CD62L 脱落来调节迁移能力，从而导致 CD62L 和 CD11b 中性粒细胞。LPS 诱导的 IL-8 释放也显著减少。用 wortmannin 抑制 PI3K 的药理学阻断拮抗了长链聚磷酸盐对 LPS 诱导的 IL-8 释放的影响。总之，聚磷酸盐控制着鼠和人中性粒细胞中的免疫调节，表明聚磷酸盐是恢复先天免疫防御的细菌感染的治疗靶点。
