Meningeal CXCL10–CXCR3 signaling contributes to postoperative cognitive dysfunction by impairing meningeal lymphatic drainage

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, but its underlying mechanisms remain incompletely understood. Meningeal lymphatic vessels (MLV) regulate cerebrospinal fluid drainage, waste clearance, and immune surveillance; however, their role in POCD remains unclear. This study aimed to determine whether impaired meningeal lymphatic drainage contributes to POCD and to explore the underlying mechanisms. Meningeal lymphatic drainage was assessed by cisterna magna tracer injection in a mouse model of POCD and by contrast-enhanced MRI in a small exploratory clinical cohort of elderly surgical patients. To determine the functional role of MLV, mice received intracisternal VEGFC to enhance meningeal lymphatic drainage or VEGFR3 d1–4 decoy receptor to disrupt meningeal lymphatic drainage. Single-cell RNA sequencing of meningeal tissues was performed to identify potential signaling pathways between macrophages and lymphatic endothelial cells. CXCL10 neutralization and CXCR3 blockade were further used to evaluate the functional role of this pathway in surgery-induced MLV dysfunction and cognitive impairment. Surgery impaired meningeal lymphatic drainage and induced postoperative cognitive deficits in aged mice. VEGFC-mediated enhancement of meningeal lymphatic drainage reduced neuroinflammation, p-tau217 accumulation, neuronal and synaptic injury, and cognitive impairment, whereas VEGFR3 d1–4 -mediated disruption of meningeal lymphatic drainage exacerbated these changes. Single-cell RNA sequencing identified the CXCL10–CXCR3 axis as a potential macrophage–lymphatic endothelial cell communication pathway. Neutralization of CXCL10 or blockade of CXCR3 improved meningeal lymphatic function and ameliorated postoperative cognitive deficits. In an exploratory clinical cohort, contrast-enhanced MRI-assessed meningeal lymphatic drainage was reduced in patients with early postoperative cognitive decline. Meningeal lymphatic dysfunction is associated with POCD and may contribute to postoperative cognitive decline by promoting neuroinflammation, p-tau217 accumulation, and neuronal and synaptic injury. Meningeal CXCL10–CXCR3 signaling may contribute to surgery-induced MLV dysfunction and may represent a potential therapeutic target for POCD.