Profiling X chromosome genes expression relevant to sex dimorphism in stroke: insights from transcriptomics landscape analysis

INTRODUCTION: Although age is the most important non-modifiable risk factor for cerebral stroke, it is also apparent that females commonly exhibit longer lifespan and better outcome after stroke compared to the age-matched males. A critical event after stroke is the peripheral infiltration of immune cells across damaged blood-brain barrier, which induces inflammatory and immune responses within the brain parenchyma and consequently worsen brain injury. These events are also dependent on age and display a sex different pattern. Theoretically, X chromosome-encoded differential expression genes (DEGs) may explain differences between the sexes. However, the expression and regulation of these DEGs after stroke have not been studied in detail. METHODS: We conducted three datasets of human blood cells, mice brain, mice microglia and T cells that were previously published, and analyzed the contribution of gender, age and stroke insult on the X chromosome-encoded DEGs. RESULTS: The main findings were (i) compared to age, the stroke/hypoxia was a more potent factor in eliciting the DEGs. Particularly, older stroke patients exhibited more changes compared to young stroke group. (ii) After a stroke, the DEGs was diversely influenced by sex, age and cell types being studied. Particularly, either aging or gender led to more striking changes in brain-infiltrating T cells than in the resident immune cells. DISCUSSION: These findings highlight the complex interplay between sex, age, and immune responses in mediating stroke incidence and outcome. Investigation of the identified X chromosome-encoded genes in brain-infiltrating T cells deserves high priority, as they may play more important roles in explaining gender-related differences in stroke and brain injury.