Nod2缺乏以性别依赖的方式加剧了母体免疫激活后代的精神分裂症相关改变。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-05-31 DOI:10.1016/j.bbi.2025.05.030

Fengjie Gao , Chuyao Wang , Zhen Cao , Xinyu Zhang , Wenyu Xi , Yixin Liu , Xianyan Zhan , Min Jia , Ningzhi Gou , Lu Yu , Yudan Zhang , Yijie Guo , Wei Wang , Feng Zhu , Xiancang Ma , Yuan Gao

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引用次数: 0

摘要

精神分裂症是一种严重的精神障碍，其发病机制复杂，涉及遗传和环境危险因素。有证据表明，免疫失调在其发展中起着关键作用，怀孕期间母体免疫激活（MIA）被认为是一个重要的环境因素。然而，并不是所有的母体感染都会导致精神分裂症样的结果，这表明遗传易感性可能使一些个体更容易患MIA。核苷酸结合寡聚化结构域蛋白2 （NOD2）是一种细胞内受体，在维持肠道微生物群和免疫应答之间的平衡中起着至关重要的作用，但其在神经发育过程中肠脑相互作用中的确切作用尚不清楚。方法：为了研究MIA与Nod2缺乏之间的相互作用，我们评估了暴露于poly（I:C）诱导MIA的Nod2-/-小鼠的行为和生理表型。除了免疫应答外，我们还分析了母体肠道微生物群以及微生物群在母体和后代之间的传播。鉴于肠-脑轴在精神分裂症中的作用，我们对胎儿大脑进行了肠道免疫荧光染色、类器官培养和RNA测序，以评估肠道损伤和大脑的神经免疫变化。雄性和雌性后代分别进行分析。结果：双重暴露导致性别特异性的精神分裂症样行为，以及大脑发育中断、肠道完整性受损、肠道类器官形成能力降低和肠道微生物群组成改变。重要的是，母体肠道微生物群紊乱，加上微生物向后代的传播，似乎会增加精神分裂症的风险，并带来潜在的长期行为后果。结论：本研究强调了遗传、环境和微生物组因素之间复杂的相互作用，为研究神经发育障碍的复杂病理生理提供了一个有价值的模型。

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Nod2 deficiency exacerbates schizophrenia-related alterations in offspring of maternal immune activation in a sex-dependent manner

Introduction

Schizophrenia is a severe mental disorder with a complex etiopathogenesis involving both genetic and environmental risk factors. Evidence suggests that immune dysregulation plays a key role in its development, with maternal immune activation (MIA) during pregnancy identified as a significant environmental contributor. However, not all maternal infections result in schizophrenia-like outcomes, indicating that genetic susceptibility may render some individuals more vulnerable to MIA. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular receptor, plays a crucial role in maintaining the balance between intestinal microbiota and immune responses, but its precise role in gut-brain interactions during neurodevelopment remain unclear.

Methods

To investigate the interaction between MIA and Nod2 deficiency, we evaluated behavioral and physiological phenotypes in Nod2^-/- mice exposed to poly(I:C)-induced MIA. In addition to immune responses, we analyzed maternal gut microbiota and the transmission of microbiota between mothers and offspring. Given the role of the gut-brain axis in schizophrenia, we conducted intestinal immunofluorescence staining, organoid cultures, and RNA sequencing of fetal brains to assess gut injury and neuroimmune changes in the brain. Male and female offspring were analyzed separately.

Results

Dual exposure led to schizophrenia-like behaviors in a sex-specific manner, as well as brain development disruptions, compromised gut integrity, reduced intestinal organoid-forming capacity, and altered gut microbiota composition. Importantly, maternal gut microbiota disturbances, coupled with microbial transmission to offspring, appear to increase schizophrenia risk with potential long-term behavioral consequences.

Conclusion

This study underscores the intricate interplay of genetic, environmental, and microbiome factors, offering a valuable model for investigating the complex pathophysiology of neurodevelopmental disorders.

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.