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

Shaohua Chen,1– 4,* Xiao Zhao,4,* Changgui Wu,5 Chin-Yun Wang,1– 3 Luying Yuan,1– 3 Lianping Xing,6 Hao Xu,1– 3 Shunchao Liu,4 Jinxia Wu,4 Jun Dai,4 Peijuan Zhou,7 Qianqian Liang,1– 3 Ning Li,1– 3 Ming Ruan,1– 3 Xiaoyun Wang1– 3,8 1Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), Shanghai, People’s Republic of China; 4Department of Education and Research, Shanghai Changning Tianshan Traditional Chinese Medicine Hospital, Shanghai, People’s Republic of China; 5Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 6Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; 7Renji Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 8Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyun Wang, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, 650 Wan-Ping South Road, Shanghai, 200032, People’s Republic of China, Email 782681050@qq.com Ming Ruan, Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, Shanghai, 200032, People’s Republic of China, Email alisonruan@163.comObjective: 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.Keywords: gouty arthritis, monosodium urate, lymphatic vessels, vascular endothelial growth factor receptor-3, inflammation