Sex Differences in Myeloid Cells

Our sex can critically impact our clinical manifestation of different diseases. Whilst this is perhaps best demonstrated in autoimmune diseases, of which 80% are found in women, throughout the human lifespan sex differences can be found in plethora of non-autoimmune related neurological disorders including: autism, attention deficit hyperactivity disorder, depression, schizophrenia, Alzheimer's and Parkinson's disease. There is strong evidence from research done in mice suggesting that microglia, brain-resident myeloid cells, may be a key driver of neurological sex differences. However, due to difficulties in their collection, it is not yet known if they play a similar role in humans. In order to determine if human microglia exhibit sexually divergent behaviors in vitro, I will be differentiating human induced pluripotent stem cells (hiPSCs) from 5 pairs of healthy male and female donors into microglia and examining their behavior following immune challenge. Their responses will characterized using a combination of transcriptomic and metabolomic profiling techniques. As sex differences will arise from the coordinated influence of the sex chromosomes and the hormonal environment, the microglia will also be pre-treated with or without the presence of exogenous 17B-estradiol, which has previously been shown to be anti-inflammatory. Furthermore, in order to determine the effects of the menstrual cycle on the inflammatory phenotype of myeloid cells, primary blood-resident macrophages will be isolated from healthy female volunteers, taken at two different time points across the menstrual cycle, and from an age-matched male donor. These will be additionally be phenotypically characterized using transcriptomic and metabolomic techniques.

The ultimate aim of this project is to identify if different response pathways are being employed by myeloid cells between the sexes both at rest and following challenge and to what extent this is influenced by estrogen. By finding which responses differ in healthy individuals, we can elicit a clearer idea of how these may be manipulated in disease, to our detriment or protection. Furthermore, this will inform the design of future study designs as to whether it is a necessity to include both sexes, and the importance that needs to be given to where women are in their menstrual cycle before drawing isolating their myeloid cells for research focused on their immune responses.