Effects of early life adversity on meningeal mast cells and proinflammatory gene expression in male and female Mus musculus

Abstract

ABSTRACTExposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.