Maternal natural killer cells drive neuroimmune disorders in offspring through aberrant secretion of extracellular granzyme B

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-05-16 DOI:10.1016/j.immuni.2025.04.028

Qiwu Bian, Yihang Chen, Jinghe Zhang, Xianghui Du, Yonggang Zhou, Qiao Zhang, Chen Ding, Haiming Wei, Binqing Fu

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Abstract

Prenatal viral infections can lead to neurodevelopmental disorders in offspring. However, how viral-induced maternal perturbations impact fetal brain macrophages remains insufficiently clear. Here, we demonstrated that inflammatory decidual natural killer (NK) cells, triggered by viral infection-induced maternal immune activation, drove macrophage activation, neurodevelopmental disorders, and behavioral deficits in offspring. Extracellular granzyme B (GzmB), predominantly released by the maternal CD49a⁺ tissue-resident NK subset under type I interferon stimulation, crossed the maternal-fetal barrier and promoted interferon-stimulated gene (ISG)-expressing fetal macrophage accumulation and microglial activation. Targeting extracellular GzmB through the systemic administration of the serine protease inhibitor Serpina3n or genetic ablation of Gzmb in maternal NK cells mitigated neuroimmune disorders in the fetal brain. These findings suggest that exposure to a perturbed maternal milieu reprograms decidual NK cell immunity, disrupting fetal neuroimmune homeostasis and increasing offspring susceptibility to neurodevelopmental disorders later in life.

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母体自然杀伤细胞通过胞外颗粒酶B的异常分泌驱动后代的神经免疫疾病

产前病毒感染可导致后代神经发育障碍。然而，病毒诱导的母体扰动如何影响胎儿脑巨噬细胞仍然不够清楚。在这里，我们证明了由病毒感染诱导的母体免疫激活引发的炎性蜕膜自然杀伤（NK）细胞驱动巨噬细胞激活、神经发育障碍和后代的行为缺陷。细胞外颗粒酶B （GzmB）主要由I型干扰素刺激下母体CD49a+组织常驻NK亚群释放，穿过母胎屏障，促进表达干扰素刺激基因（ISG）的胎儿巨噬细胞积累和小胶质细胞活化。通过全身给药丝氨酸蛋白酶抑制剂Serpina3n或基因消融母体NK细胞中的GzmB靶向细胞外GzmB可减轻胎儿大脑的神经免疫疾病。这些发现表明，暴露于受干扰的母体环境中会重编程个体NK细胞免疫，破坏胎儿神经免疫稳态，增加后代在以后的生活中对神经发育障碍的易感性。

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.