Lymphatic Vessels are Involved in Monosodium Urate Clearance and Resolution of Gouty Inflammation in Mice

Objective: To investigate the potential role of lymphatic system in gouty arthritis (GA) by integrating clinical observations in human draining lymph nodes with functional studies in a mouse model. Methods: We first conducted ultrasound examinations of draining lymph nodes in 30 GA patients and 30 healthy controls. Subsequently, we established mouse models of acute and chronic GA via monosodium urate (MSU) crystal injection. Lymphatic nodes were assessed using ultrasound, the structure and function of lymphatic vessels were assessed using histology and near-infrared imaging. We further employed a VEGFR-3 inhibitor to disrupt lymphatic function and evaluated its impact on inflammatory resolution in MSU-induced GA mouse model. Results: Patients with GA showed significantly larger draining lymph nodes compared with healthy controls, a finding also observed in MSU-induced GA mouse model. The concentration of uric acid in the draining lymph nodes after MSU injection was significantly elevated and exceeded that in the serum. The structure of lymphatic vessels in paw tissues was impaired, and the draining function was reduced during the inflammatory process induced by MSU injection at 1 and 4 weeks. Lymphatic vessel leakage was observed after 4 weeks of MSU treatment. Critically, pharmacological inhibition of VEGFR-3, which disrupted lymphatic integrity, subsequently delayed the resolution of MSU-induced inflammation. Conclusion: Our findings in humans demonstrate a clinical association between GA and lymphatic system engagement. Mouse studies highlight a dual and critical role of the lymphatic system in GA pathogenesis: it is involved in clearance but vulnerable to damage, which may perpetuate inflammation.