Multi-omics analysis reveals the neuroprotective effects of phosphatidylcholine (18:1/18:2) on ischemic stroke by inhibiting plasma IL-18 levels.

Abstract

BACKGROUND: Observational studies show significant differences in plasma lipid profiles between ischemic stroke (IS) patients and healthy individuals, but the causal relationships are unclear. This study aimed to explore the causal links between 179 plasma lipid species and IS and investigate the role of inflammatory proteins as mediators in this relationship. We also analyzed inflammatory protein expression in the brain before and after stroke. METHODS: We utilized publicly available genome-wide association study (GWAS) data for a two-sample Mendelian randomization (MR) analysis using inverse variance-weighted (IVW) methods, supplemented by weighted median and MR-Egger approaches. Additionally, single-cell and transcriptome sequencing data were collected from mouse models of middle cerebral artery occlusion (MCAO) and control samples to assess inflammatory protein expression changes. RESULTS: The MR analysis revealed that higher levels of phosphatidylcholine (PC) (18:1/18:2) were associated with a reduced risk of IS (OR = 0.816, 95 % CI 0.742-0.898, p = 2.89 × 10-5). Interleukin (IL)-18 was identified as a mediator in this association, with a mediation proportion of 4.07 %. During stroke onset, IL-18 expression increased significantly in CNS-associated macrophages and other cell types but was lower in homeostatic microglial cells. CONCLUSION: Our findings suggest that PC (18:1/18:2) may reduce IL-18 levels and, consequently, the risk of IS. Enhancing beneficial plasma lipid levels might be a promising strategy for stroke prevention and recovery.