Analysis of sex specific differences in glial cells affecting macrophage invasion of the fly brain

影响果蝇大脑巨噬细胞侵袭的胶质细胞性别特异性差异分析

• 批准号: 520050892
• 负责人: Professor Dr. Christian Klämbt
• 金额: --
• 依托单位: Institut für Neuro- und Verhaltensbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/520050892?language=en
• 关键词: Analysis; sex; specific; differences; glial

To ensure proper homeostatic function within the brain, the nervous system is separated from the circulatory system by the blood-brain barrier (BBB) which is either formed by glial or endothelial cells. In addition, the BBB prevents the invasion of pathogens and immune cells. Due to its efficient separation from circulation, the nervous system is considered an immune-privileged organ. Thus, specific cellular defense mechanisms have evolved to cope with infections and the removal of cellular debris within the CNS. In invertebrates, it was previously thought that CNS glial cells clear cellular debris, whereas macrophages fight pathogens primarily in the hemolymph. However, as we recently demonstrated, hemolymph-derived macrophages are also able to invade an inflamed fly brain, where they cross two separate barriers of the CNS: The blood-brain barrier formed by perineurial and the subperineurial glial cells and an barrier around the neuropil formed by the ensheathing glia. Surprisingly, we found that macrophages invade the male brain more easily than the female brain. Preliminary data suggest that this is due to sex-specific differences in the blood-brain barrier. Here we want to decipher the mechanisms underlying sex-specific differences in glial differentiation and how this could influence macrophage invasion. Previous sequencing projects have identified several candidates expressed in a sex specific manner in these glial cells. We will test whether these genes make male brains more susceptible to macrophage invasion upon glial immunity induction. To thoroughly address sex-specific differences in the different glial cells of the CNS, we will perform sequence analyses at time periods relevant for macrophage invasion. Candidate genes will then be analyzed.

为了确保大脑内正常的内稳态功能，神经系统与循环系统被血脑屏障（BBB）隔开，血脑屏障由神经胶质细胞或内皮细胞形成。此外，血屏障还能阻止病原体和免疫细胞的入侵。由于神经系统与循环系统的有效分离，它被认为是一种免疫特权器官。因此，特定的细胞防御机制已经发展到应对感染和清除中枢神经系统内的细胞碎片。在无脊椎动物中，以前认为中枢神经胶质细胞清除细胞碎片，而巨噬细胞主要在血淋巴中对抗病原体。然而，正如我们最近所证明的那样，血淋巴来源的巨噬细胞也能够侵入发炎的苍蝇大脑，在那里它们穿过两种不同的中枢神经系统屏障：由神经周围和神经周围胶质细胞形成的血脑屏障，以及由鞘层胶质细胞形成的神经周围屏障。令人惊讶的是，我们发现巨噬细胞比女性更容易侵入男性大脑。初步数据表明，这是由于血脑屏障的性别差异造成的。在这里，我们想要破译神经胶质分化中性别特异性差异的机制，以及这如何影响巨噬细胞的侵袭。先前的测序项目已经确定了在这些胶质细胞中以性别特异性方式表达的几种候选基因。我们将测试这些基因是否使男性大脑更容易受到神经胶质免疫诱导的巨噬细胞入侵。为了彻底解决中枢神经系统不同胶质细胞的性别特异性差异，我们将在巨噬细胞入侵相关的时间段进行序列分析。然后对候选基因进行分析。