A causal glycerophospholipid-IL-18R1-CD9 axis connects lipid metabolism and T-cell activation in atopic dermatitis

Atopic dermatitis (AD) involves complex metabolic-immune dysregulation, but the molecular links remain unclear. This study integrates a multilevel analytical framework to systematically investigate the metabolic-immune crosstalk in AD. Using linkage disequilibrium score regression and a two-step Mendelian randomization approach, we established genetic correlations and inferred causal relationships between plasma metabolites and inflammatory proteins, identifying 1-palmitoyl-2-arachidonoyl-GPC (PA-GPC) as a protective metabolite that exerts its effect primarily through downregulation of interleukin-18 receptor 1 (IL-18R1). Integration of single-cell transcriptomic data further revealed elevated IL-18R1 expression in T cells within the AD microenvironment and enabled stratification of T cells based on PA-GPC-associated metabolic activity, identifying 33 differentially expressed genes. Subsequent least absolute shrinkage and selection operator (LASSO) regression, combined with machine learning models and SHapley Additive exPlanations analysis, consistently prioritized CD9 as a key regulator. Functional validation showed that PA-GPC attenuates tumor necrosis factor-alpha (TNF-α)/interferon-gamma (IFN-γ)-induced inflammatory responses in human immortalized keratinocyte (HaCaT) cells and suppresses Th2 cytokine production in T cells. IL-18R1 knockdown reduced CD9 expression and Th2 cytokine production in T cells, whereas CD9 knockdown did not affect IL-18R1 expression, indicating that IL-18R1 acts upstream of CD9. Moreover, CD9 knockdown impaired T-cell viability, activation, and Th2 cytokine production. Collectively, these findings characterize metabolic-immune crosstalk in AD and identify a PA-GPC-IL-18R1-CD9 regulatory axis with potential therapeutic implications.