Sex differences in ex vivo cytokine production and their association with outcome following ischemic stroke.

BACKGROUND

Animal studies suggest that post-stroke inflammatory responses are sexually dimorphic and may influence recovery. We examined whether men and women with acute ischemic stroke differ in ex vivo cytokine synthesis and whether such differences relate to functional outcome.

METHODS

We included 279 patients with acute ischemic stroke (mean age: 68.5 ± 12.8; 41.2% women). Blood samples collected on day 3 after stroke were stimulated with lipopolysaccharide (LPS). Ex vivo production of TNFα, IP-10, IL-1β, IL-6, IL-8, IL-10, and IL-12p70 was measured using enzyme-linked immunoassay or cytometric methods, and expression of LPS-induced cytokine and chemokine genes was assessed by RNA sequencing.

RESULTS

Greater stroke severity, lower monocyte counts, and the use of angiotensin receptor blockers were associated with decreased production of pro-inflammatory cytokines. Compared with females, males showed higher ex vivo synthesis of TNFα (mean: 2814.2 vs 2302.7 pg/mL, P = 0.003), IL-1β (1851.9 vs 1461.3 pg/mL, P = 0.002), IL-6 (14345.3 vs 11846.5 pg/mL, P = 0.004), IL-12 (7.1 vs 4.2 pg/mL, P = 0.002), and IP-10 (557.9 vs 435.1 pg/mL, P = 0.038), with correspondingly higher gene expression levels of TNFα, IL-1β, IL-6, and IL-12. In multivariable quantile regression models adjusted for cytokine-specific covariates, male sex remained significantly associated with higher levels of TNFα, IL-1β, and IL-6. Despite this sex-related difference in inflammatory response, three-month functional outcomes were similar in men and women.

CONCLUSION

Males exhibited greater ex vivo pro-inflammatory cytokine production after ischemic stroke, but this sexual dimorphism did not translate into differences in functional recovery.