Sex differences in the inflammatory response to stroke

Abstract

Ischemic stroke is a leading cause of morbidity and mortality and disproportionally affects women, in part due to their higher longevity. Older women have poorer outcomes after stroke with high rates of cognitive deficits, depression, and reduced quality of life. Post-stroke inflammatory responses are also sexually dimorphic and drive differences in infarct size and recovery. Factors that influence sex-specific immune responses can be both intrinsic and extrinsic. Differences in gonadal hormone exposure, sex chromosome compliment, and environmental/social factors can drive changes in transcriptional and metabolic profiles. In addition, how these variables interact, changes across the lifespan. After the onset of ischemic injury, necrosis and apoptosis occur, which activate microglia and other glial cells within the central nervous system, promoting the release of cytokines and chemokines and neuroinflammation. Cells involved in innate and adaptive immune responses also have dual functions after stroke as they can enhance inflammation acutely, but also contribute to suppression of the inflammatory cascade and later repair. In this review, we provide an overview of the current literature on sex-specific inflammatory responses to ischemic stroke. Understanding these differences is critical to identifying therapeutic options for both men and women.

Keywords: Ischemic stroke; Neuroinflammation; Sex differences; Sex hormones.

Fig. 1

Adaptive immune responses regulated by T and B cells in stroke. (created with BioRender.com)

Fig. 2

Sex differences in microglial response following stroke. Female microglia confer neuroprotection in stroke by secreting higher levels of anti-inflammatory cytokines including IL-4 and IL-10 and lower proinflammatory cytokines including IL-1β, IL-6, and TNF-α, compared with male microglia (created with BioRender.com)

Fig. 3

Sex differences in the systemic T cell response following stroke. Tian et al. [188] profiled gene expression in the blood from male and female ischemic stroke patients (≤ 3, 5, and 24 h) and performed functional analysis to identify pathways. Of note, female-specific pathways include T-helper cell differentiation and regulation of T cell activation. Canonical pathways and GO biological process for ≤ 3 h after stroke were shown here. In a mouse model of stroke, females had higher regulatory T cells in the blood compared with males [74] (created with BioRender.com)