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

• Applicant: Professor Dr. Christian Klämbt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 520050892

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.

• DFG Programme: Research Grants