Mi Yang

Rheumatoid arthritis (RA) is sustained not only by immune activation within the synovium but also by dysfunction of the lymphatic network that normally clears interstitial fluid, inflammatory mediators, and leukocytes migrating from inflamed tissues. Functional abnormalities in lymph node stromal cells may arise before clinically apparent arthritis. After RA becomes established, the lymphatic response may shift from compensatory lymphangiogenesis to reduced collecting-vessel contraction, structural deterioration of draining lymph nodes, and impaired lymphatic drainage. This review examines how IL-33/ST2 signaling, neutrophil extracellular traps (NETs), and the lymphatic endothelial program maintained by PROX1 may influence the shift from compensatory remodeling to lymphatic dysfunction. During early inflammation, IL-33 can activate the ST2/TRAF6/PI3K/Akt/eNOS/NO pathway in lymphatic endothelial cells (LECs), while VEGF-C/VEGFR3 signaling supports lymphatic vessel growth and fluid transport. But vessel expansion does not guarantee that newly formed lymphatics mature or restore effective drainage. As inflammation persists, TNF-driven iNOS activity, occupation of lymphatic sinuses by B cells, and structural changes in draining lymph nodes can reduce lymphatic transport and prolong synovial exposure to cytokines, immune complexes, and autoantigens. NETs directly injure lymphatic endothelium in inflammatory models outside RA, but direct evidence in synovial LECs remains unavailable. NET-associated histones, proteases, myeloperoxidase, extracellular DNA, and HMGB1 should therefore be considered plausible rather than established mediators of LEC injury through junctional disruption, oxidative stress, or RAGE- and TLR9-related signaling. Reduced PROX1 activity may further weaken lymphatic endothelial identity by disrupting the expression of VEGFR3, LYVE1, PDPN, and CCL21, which support vessel maintenance and immune-cell transport. Based on these findings, we propose a stage-dependent model in which established IL-33–NET–fibroblast-like synoviocyte and IL-33–macrophage circuits increase the inflammatory burden, while declining lymphatic clearance retains the mediators that sustain these circuits. This framework separates demonstrated mechanisms from untested links and identifies synovial LEC injury, lymphatic transport, and stage-specific pathway modulation as priorities for mechanistic studies and therapeutic development.

Rheumatoid arthritis (RA) is sustained not only by immune activation within the synovium but also by dysfunction of the lymphatic network that normally clears interstitial fluid, inflammatory mediators, and leukocytes migrating from inflamed tissues. Functional abnormalities in lymph node stromal cells may arise before clinically apparent arthritis. After RA becomes established, the lymphatic response may shift from compensatory lymphangiogenesis to reduced collecting-vessel contraction, structural deterioration of draining lymph nodes, and impaired lymphatic drainage. This review examines how IL-33/ST2 signaling, neutrophil extracellular traps (NETs), and the lymphatic endothelial program maintained by PROX1 may influence the shift from compensatory remodeling to lymphatic dysfunction. During early inflammation, IL-33 can activate the ST2/TRAF6/PI3K/Akt/eNOS/NO pathway in lymphatic endothelial cells (LECs), while VEGF-C/VEGFR3 signaling supports lymphatic vessel growth and fluid transport. But vessel expansion does not guarantee that newly formed lymphatics mature or restore effective drainage. As inflammation persists, TNF-driven iNOS activity, occupation of lymphatic sinuses by B cells, and structural changes in draining lymph nodes can reduce lymphatic transport and prolong synovial exposure to cytokines, immune complexes, and autoantigens. NETs directly injure lymphatic endothelium in inflammatory models outside RA, but direct evidence in synovial LECs remains unavailable. NET-associated histones, proteases, myeloperoxidase, extracellular DNA, and HMGB1 should therefore be considered plausible rather than established mediators of LEC injury through junctional disruption, oxidative stress, or RAGE- and TLR9-related signaling. Reduced PROX1 activity may further weaken lymphatic endothelial identity by disrupting the expression of VEGFR3, LYVE1, PDPN, and CCL21, which support vessel maintenance and immune-cell transport. Based on these findings, we propose a stage-dependent model in which established IL-33–NET–fibroblast-like synoviocyte and IL-33–macrophage circuits increase the inflammatory burden, while declining lymphatic clearance retains the mediators that sustain these circuits. This framework separates demonstrated mechanisms from untested links and identifies synovial LEC injury, lymphatic transport, and stage-specific pathway modulation as priorities for mechanistic studies and therapeutic development.