自闭症患者 iPSC 衍生的小胶质细胞中 NRXN1α 的双等位缺失会增加白细胞介素-6 的产生并损害对神经元网络的支持功能。

IF 8.8 2区 医学 Q1 IMMUNOLOGY
Raj Bose , Mercedes Posada-Pérez , Eleni Karvela , Martin Skandik , Lily Keane , Anna Falk , Stefan Spulber , Bertrand Joseph , Sandra Ceccatelli
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引用次数: 0

摘要

自闭症谱系障碍(ASD)是一组异质性神经发育疾病,具有高度多样化的遗传因素,包括神经元回路的改变,对患者的交流技能和行为产生影响。除了公认的神经元改变的作用外,小胶质细胞的扰动和相关的神经炎症过程也是导致 ASD 病因学和生理病理学的可信因素。NRXN1是与神经胶质蛋白结合的细胞表面受体神经胶质蛋白家族的成员,其突变与ASD有关。众所周知,NRXN1 在神经元中表达,可促进突触接触,但在包括小胶质细胞在内的胶质细胞中也被发现。确定 ASD 相关基因对神经元和小胶质细胞功能的影响一直是个挑战。在这里,我们提出了一种基于体外系统的 ASD 受试者诱导多能干细胞(iPSC),以描述 ASD 相关 NRXN1 基因缺失对神经元和小胶质细胞的影响,以及对小胶质细胞支持神经元回路形成和功能的能力的影响。利用这种方法,我们证明了 NRXN1 基因缺失会影响小胶质细胞中α异构体(NRXN1α)的表达,从而导致小胶质细胞的改变和 IL6(一种与 ASD 相关的促炎性白细胞介素)的释放。此外,NRXN1α缺失的小胶质细胞失去了支持功能性神经元网络形成的能力。在对照小胶质细胞-神经元共培养物上使用重组IL6蛋白,或在NRXN1α缺失的小胶质细胞-神经元共培养物上使用IL6中和抗体,都证实了IL6对所观察到的神经元表型有直接作用。总之,我们的数据表明,除神经元外,小胶质细胞也受到 NRXN1α 缺失的负面影响,这在很大程度上导致了所观察到的神经元回路畸变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bi-allelic NRXN1α deletion in microglia derived from iPSC of an autistic patient increases interleukin-6 production and impairs supporting function on neuronal networking

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions, with a highly diverse genetic hereditary component, including altered neuronal circuits, that has an impact on communication skills and behaviours of the affected individuals. Beside the recognised role of neuronal alterations, perturbations of microglia and the associated neuroinflammatory processes have emerged as credible contributors to aetiology and physiopathology of ASD. Mutations in NRXN1, a member of the neurexin family of cell-surface receptors that bind neuroligin, have been associated to ASD. NRXN1 is known to be expressed by neurons where it facilitates synaptic contacts, but it has also been identified in glial cells including microglia. Asserting the impact of ASD-related genes on neuronal versus microglia functions has been challenging. Here, we present an ASD subject-derived induced pluripotent stem cells (iPSC)-based in vitro system to characterise the effects of the ASD-associated NRXN1 gene deletion on neurons and microglia, as well as on the ability of microglia to support neuronal circuit formation and function. Using this approach, we demonstrated that NRXN1 deletion, impacting on the expression of the alpha isoform (NRXN1α), in microglia leads to microglial alterations and release of IL6, a pro-inflammatory interleukin associated with ASD. Moreover, microglia bearing the NRXN1α-deletion, lost the ability to support the formation of functional neuronal networks. The use of recombinant IL6 protein on control microglia-neuron co-cultures or neutralizing antibody to IL6 on their NRXN1α-deficient counterparts, supported a direct contribution of IL6 to the observed neuronal phenotype. Altogether, our data suggest that, in addition to neurons, microglia are also negatively affected by NRXN1α-deletion, and this significantly contributes to the observed neuronal circuit aberrations.

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来源期刊
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.
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