Inflammatory-immune crosstalk in aneurysmal subarachnoid hemorrhage: bidirectional Mendelian randomization and causal...

The causal interplay between inflammatory mediators and immune cell phenotypes in aneurysmal subarachnoid hemorrhage (aSAH) remains undefined. We investigated whether immune surface antigens influence rupture risk through inflammatory protein mediation.

Using European genetic consortium data, we implemented an integrated Mendelian randomization (MR) framework. First, univariable MR assessed effects of 731 immune cell traits and 91 inflammatory proteins on rupture risk. Second, two-step MR quantified mediation effects where exposures influenced both mediator and outcome. Third, multivariable MR determined direct effects after mediator adjustment. Sensitivity analyses controlled for smoking, systolic blood pressure, and lipid levels.

Elevated CD4 abundance on plasma CD28+ CD4+ T cells reduced rupture risk [OR (odds ratio) = 0.901; p = 0.004]. Serum CX3CL1 mediated 12% of this protection (OR _mediation = 0.987; two-step MR p < 0.05). The direct protective effect persisted after CX3CL1 adjustment (OR _direct = 0.913; multivariable MR p = 0.013).Separately, interleukin-7 demonstrated strong independent risk effects (OR = 2.027; p = 1.29×10^{- 4}, Bonferroni-corrected). Our comprehensive screen additionally identified multiple immuno-inflammatory factors significantly associated with aSAH risk (univariable MR p<0.05), further evidencing the complex immunoinflammatory network in rupture pathogenesis. No pathway showed significant confounding by cardiometabolic factors.

We establish a novel immune-inflammatory axis wherein CD4+ T cell surface signatures confer protection against intracranial aneurysm rupture partially through CX3CL1 downregulation, while interleukin-7 independently promotes rupture. These findings reveal actionable targets for risk stratification and immunomodulatory interventions.