The Francis Crick Institute, Antimicrobial Defence Laboratory, London, UK.
The Francis Crick Institute, Bioinformatics and Biostatistics, London, UK.
Nat Commun. 2022 Aug 9;13(1):4658. doi: 10.1038/s41467-022-32320-1.
The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology, but their source and mechanism of action remain unclear. Here, we show that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release. Histones and hyphae induce cytokines in adjacent CD169 macrophages including G-CSF that selectively depletes mature Ly6G neutrophils by shortening their lifespan in favour of immature Ly6G neutrophils with a defective oxidative burst. In sepsis patient plasma, these mediators shorten mature neutrophil lifespan and correlate with neutrophil mortality markers. Consequently, high G-CSF levels and neutrophil lifespan shortening activity are associated with sepsis patient mortality. Hence, by exploiting phagocytic receptors, pathogens degrade innate and adaptive immunity through the detrimental impact of downstream effectors on neutrophil lifespan.
全身性感染与脓毒症中过度炎症和免疫功能障碍的相关机制尚未完全阐明。细胞外组蛋白促进脓毒症的病理发生，但它们的来源和作用机制仍不清楚。在这里，我们发现中性粒细胞髓过氧化物酶通过控制被脾巨噬细胞捕获的真菌和细菌，从而抑制组蛋白释放，来减轻脓毒症。在系统性念珠菌病中，吞噬受体 SIGNR1 通过促进边缘区浸润和 T 细胞死亡依赖的组蛋白释放，来中和髓过氧化物酶。组蛋白和菌丝诱导相邻 CD169 巨噬细胞中的细胞因子，包括 G-CSF，通过缩短其寿命有利于具有缺陷氧化爆发的不成熟 Ly6G 中性粒细胞，从而选择性地耗尽成熟 Ly6G 中性粒细胞。在脓毒症患者的血浆中，这些介质缩短了成熟中性粒细胞的寿命，并与中性粒细胞死亡率标志物相关。因此，高 G-CSF 水平和中性粒细胞寿命缩短活性与脓毒症患者的死亡率相关。因此，病原体通过下游效应物对中性粒细胞寿命的有害影响，利用吞噬受体破坏固有和适应性免疫。
