Role and mechanism of fibroblast FMO2 in regulating B cell recruitment in pulmonary arterial hypertension

Background and Purpose FMO2, a key member of the flavin-containing monooxygenase family, is crucial in drug metabolism and environmental toxin detoxification. In pulmonary arterial hypertension (PAH), a disease with no effective treatment for vascular remodeling, FMO2 expression is notably high in lung tissue. Our previous studies showed that FMO2 overexpression alleviated bleomycin-induced fibrosis, suggesting a potential role in PAH. Fibroblasts, which regulate immune responses and cytokine secretion, may influence PAH progression. B cells, which promote vascular remodeling in PAH, interact with fibroblasts via CXCL13, a chemokine that drives B cell migration. This study explores whether FMO2 regulates CXCL13 expression in fibroblasts through ETV1, affecting B cell recruitment in PAH. Methods and Results FMO2 expression was significantly lower in PAH lung tissue compared to healthy controls. In animal models, FMO2 knockout exacerbated PAH, increasing pulmonary artery pressure and vascular remodeling. FMO2 knockout in fibroblasts specifically elevated CXCL13 expression and B cell infiltration. CXCL13 knockdown in these fibroblasts alleviated PAH features and reduced B cell recruitment. FMO2 knockdown in fibroblasts enhanced B cell chemotaxis and CXCL13 expression, while overexpression suppressed both. RNA-seq analysis identified ETV1 as a key transcription factor regulating CXCL13. ETV1 knockdown reduced CXCL13 levels and B cell chemotaxis. Conclusion FMO2 regulates CXCL13 expression in fibroblasts via ETV1, influencing B cell recruitment in PAH. These findings suggest that FMO2 plays a critical role in PAH pathogenesis, providing a potential therapeutic target.