Chemerin介导巨噬细胞焦亡导致妊娠期糖尿病子代脑损伤的机制研究

The data of clinical and epidemiological investigations show that gestational diabetes mellitus (GDM) is asscociated with fetal nervous system dysplasia, however, the mechanism is unclear. In our previous research, it was found that Chemerin, an adipocytokine, was in higher level among women with GDM, and this adipocytokine could achieve a high local level in brain by binding to CC-chemokine receptor-like 2（CCRL2）, an atypical receptor of Chemerin which might express in the brain cells. Besides, with binding to the specific receptor of Chemerin, ChemR23, Chemerin was found to induce the chemotaxis migration of macrophages which ultimately infiltrated in the brain of mice’ fetuses, and subsequently the expression of components related to cell pyroptosis increased, with the release of proinflammatory factors. Our research findings suggested that the pyroptosis of macrophages mediated by Chemerin might be one of the pathways to fetal nervous system dysplasia from GDM women. Therefore, this study aims to reveal the very mechanism by exploring the process of Chemerin gathering in brain and its influence on the migration, gathering and infiltration of macrophages, as well as studying the molecular regulation that how ChemR23 mediates the pyroptosis of macrophages, which lead to the inflammation response and neuronal injury of neonatal brain from women with GDM. The expected results will lay a new theoretical foundation on exploring the mechanism of brain injury of offspring of women with GDM, and provide more intervention targets and measures for preventing adverse perinatal outcomes.

研究表明妊娠期糖尿病（GDM）子代神经系统发育不良风险增加，但其具体机制不明。课题组前期研究发现GDM体内脂肪细胞因子Chemerin水平升高，并通过与其非典型受体CCRL2的结合富集于胎儿脑部，再通过其特异性受体ChemR23趋化巨噬细胞迁移至脑组织，后者表现为细胞焦亡相关组分表达增加并伴有炎症因子的大量释放，提示GDM子代脑损伤或与Chemerin介导的巨噬细胞焦亡有关。为探明其机制，本研究拟从不同层次探讨GDM体内Chemerin利用CCRL2富集于子代脑组织的具体过程；揭示Chemerin趋化巨噬细胞穿过血脑屏障，并激活细胞焦亡导致子代脑损伤的内在机制，进一步探索抑制CCRL2、ChemR23及细胞焦亡特征蛋白Caspase-1的表达是否可以修复子代脑损伤。研究结果有利于阐明Chemerin对GDM子代脑损伤的机制，为干预GDM子代不良围产结局提供潜在的靶点和理论依据。

研究表明妊娠期糖尿病（GDM）子代神经系统发育不良风险增加，但其机制不明。本研究立足研究背景，结合前期研究基础，提出了GDM子代体内chemerin诱导巨噬细胞浸润脑组织并发生焦亡、导致其神经组织炎性损伤和认知功能改变的科学猜想，并从细胞学、动物组织学及行为学多水平加以验证。本研究通过腹腔注射chemerin建立了新的GDM模型，并发现GDM的子代的脑组织神经元数量下降，认知功能受损；在对此现象的潜在机制的探索中，本研究发现GDM子代脑组织中chemerin水平显著上升，chemerin的上升主要由其不典型受体CCRL2介导，chemerin水平上升后可通过其主要受体chemR23募集巨噬细胞的大量浸润脑组织，被募集的巨噬细胞焦亡水平及炎症因子明显上升，相应神经组元的数量显著下降，子代的认知功能受损；而敲降CCRL2或chemR23后，chemerin介导的子代脑组织神经元下降和认知功能改变得到部分缓解。本研究最终阐明了GDM致子代认知功能异常的潜在机制之一：chemerin通过CCRL2实现了在子代脑组织中的富集，并通过chemR23募集巨噬细胞浸润，诱发焦亡和炎症反应，导致神经组织炎性损伤和认知功能改变。本研究为进一步阐明GDM子代脑损伤的机制奠定了理论基础，为干预GDM子代不良围产结局提供了潜在的靶点和理论依据。