Phenotypic characterisation of sex differences in myeloid cells

Abstract

Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease, for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in pathogenesis of this disease. We hypothesised that sex differences in the phenotype of human myeloid cell populations may contribute to the sex difference observed in Alzheimer’s disease prevalence. To explore this, bulk and single-nuclear RNA sequencing datasets were analysed from four human myeloid cell populations: peripheral monocyte-derived macrophages (MDMs), peripheral monocytes, induced pluripotent stem cell derived microglial-like cells (MGLs), and post-mortem microglia. The MDMs and MGLs were additionally treated with lipopolysaccharide (LPS) to induce an inflammatory response, with both naïve and LPS treated cells harvested for sequencing and metabolomic assays. We found that the expression of genes related to proinflammatory immune responses and gene signatures associated with Alzheimer’s disease were consistently enriched in myeloid cells isolated from female donors. Expression of these gene sets did not significantly differ between the female MDMs across the menstrual cycle nor in MGLs cultured with 17β-oestradiol, suggesting that the consistent female enrichments observed were not driven by acute hormonal influences. Moreover, treatment with LPS exhibited limited influence on the transcriptional sex differences observed. Contrasting expectations from mouse models, treatment with LPS was also not found to exert a substantial influence on the metabolic profile of either MDMs or MGLs, in which limited sex differences were identified in both naïve and LPS treated conditions. Those discovered, however, suggested augmented metabolism of pyrimidines and purines in naïve male cells associated with a higher energy state. Together, these data support the hypothesis that the increased prevalence of Alzheimer’s disease in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to Alzheimer’s disease