Institute of Cardiovascular Physiology and Pathophysiology, Walter-Brendel-Center of Experimental Medicine, Biomedical Center Munich, LMU Munich, Planegg-Martinsried, Germany.
Division of Neonatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU Munich, Munich, Germany.
JCI Insight. 2023 Feb 22;8(4):e155968. doi: 10.1172/jci.insight.155968.
Newborns are at high risk of developing neonatal sepsis, particularly if born prematurely. This has been linked to divergent requirements the immune system has to fulfill during intrauterine compared with extrauterine life. By transcriptomic analysis of fetal and adult neutrophils, we shed new light on the molecular mechanisms of neutrophil maturation and functional adaption during fetal ontogeny. We identified an accumulation of differentially regulated genes within the noncanonical NF-κB signaling pathway accompanied by constitutive nuclear localization of RelB and increased surface expression of TNF receptor type II in fetal neutrophils, as well as elevated levels of lymphotoxin α in fetal serum. Furthermore, we found strong upregulation of the negative inflammatory regulator A20 (Tnfaip3) in fetal neutrophils, which was accompanied by pronounced downregulation of the canonical NF-κB pathway. Functionally, overexpressing A20 in Hoxb8 cells led to reduced adhesion of these neutrophil-like cells in a flow chamber system. Conversely, mice with a neutrophil-specific A20 deletion displayed increased inflammation in vivo. Taken together, we have uncovered constitutive activation of the noncanonical NF-κB pathway with concomitant upregulation of A20 in fetal neutrophils. This offers perfect adaption of neutrophil function during intrauterine fetal life but also restricts appropriate immune responses particularly in prematurely born infants.
新生儿极易发生新生儿败血症，尤其是早产儿。这与免疫系统在宫内与宫外生活中必须满足的不同要求有关。通过对胎儿和成人中性粒细胞的转录组分析，我们揭示了中性粒细胞成熟和功能适应的分子机制在胎儿发育过程中的变化。我们发现，非典型 NF-κB 信号通路中的差异调节基因积累，RelB 持续核定位，TNF 受体 II 表面表达增加，胎儿中性粒细胞中也存在淋巴毒素α水平升高。此外，我们发现胎儿中性粒细胞中抗炎调节剂 A20（Tnfaip3）的强烈上调，同时经典 NF-κB 途径明显下调。功能上，在 Hoxb8 细胞中过表达 A20 导致这些中性粒细胞样细胞在流动室系统中的粘附减少。相反，具有中性粒细胞特异性 A20 缺失的小鼠体内炎症增加。综上所述，我们发现胎儿中性粒细胞中存在非典型 NF-κB 通路的持续激活，同时 A20 的表达上调。这为胎儿在宫内生活中的中性粒细胞功能提供了完美的适应，但也限制了特别是早产儿的适当免疫反应。
