Abstract DP092: Sex-specific Difference in IL-6 Signaling Pathway after Acute Ischemic Stroke

Introduction: Epidemiological studies have shown sex differences in stroke prevalence and outcomes. These differences may be attributed, in part, to sex-specific immune responses that alter post-stroke inflammatory events. Inflammation is a hallmark of stroke pathology, and cytokines such as interleukin-6 (IL-6) and its receptor (IL-6R) play critical roles in modulating tissue damage. IL-6R is cleaved by the metalloprotease ADAM17, generating a soluble form (sIL-6R) that binds IL-6 to form IL-6 and sIL-6R complexes. These complexes activate pro-inflammatory IL-6 trans-signaling through the ubiquitous glycoprotein 130 receptor (gp130). Although growing evidence points to significant sex differences in post-stroke inflammation, this area remains understudied. Hypothesis: We hypothesize that IL-6 signaling is differentially regulated in males and females after stroke, reflecting sex-specific immune responses that may underlie disparities in recovery, risk of complications, and long-term outcomes. Methods: Plasma samples from ischemic stroke patients were collected 24 hours after the last known well time. IL-6R (n=233; 67±14 y; 108 females, 125 males), IL-6 (n=157; 68±12 y; 71 females, 86 males), ADAM17 (n=125; 68±12 y; 57 females, 68 males), and gp130 (n=114; 69±12 y; 58 females, 56 males) levels were quantified using ELISA, following the manufacturers' protocols. All patients had imaging confirmed strokes. Results: Plasma levels of IL-6R and IL-6 were significantly higher in females compared to males (p=0.049 and p=0.034, respectively), suggesting enhanced IL-6 signaling. In contrast, ADAM17 levels were significantly lower in females (p=0.019). No significant sex differences were observed in gp130 levels. Conclusion: These findings underscore significant sex-specific differences in post-stroke inflammation, with IL-6 signaling emerging as a potential contributor to disparities in recovery and long-term outcomes. Understanding the mechanisms underlying these differences is crucial for developing targeted therapies and addressing sex-based disparities in stroke outcomes.