Department of Paediatrics, School of Medicine, University of Crete, Heraklion, Greece.
Institute of Molecular Biology and Biotechnology, IMMB, FORTH, Heraklion, Greece.
Nat Commun. 2024 Jan 23;15(1):680. doi: 10.1038/s41467-023-44178-y.
The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life.
中性粒细胞储备有限与新生儿易感染有关，但早期感染中中性粒细胞动力学的调节仍知之甚少。在这里，我们表明发育内皮基因座（DEL-1）在新生儿中升高，并且通过支持紧急粒状细胞生成对于从新生儿多微生物败血症中存活至关重要。患有败血症的 DEL-1 缺陷型新生小鼠在骨髓中显示出数量较少的偏骨髓多能性和粒细胞-巨噬细胞祖细胞，导致中性粒细胞减少症、菌血症加剧和死亡率增加；这些缺陷可通过 DEL-1 给药来挽救。在新生儿败血症中观察到的高 IL-10/IL-17A 比值维持组织 DEL-1 表达，因为 IL-10 上调而 IL-17 下调 DEL-1。一致地，在具有高血清 IL-10/IL-17A 比值的败血症成人和新生儿患者中，血清 DEL-1 和血液中性粒细胞升高，并且具有高血清 DEL-1 的败血症患者的死亡率较低。因此，IL-10/DEL-1 轴支持紧急粒状细胞生成，防止中性粒细胞减少症并促进早期生命中的败血症存活。
