Fig. 1

Immune regulation roles of lymphangiogenesis in inflammation settings. a. During kidney inflammation, lymphangiogenesis is significantly induced, and LECs overexpress chemokine CCL21, which promotes recruitment of CCR7⁺ immune cells to kidney dLNs through lymphatic vessels. Increased migration of CCR7⁺ dendritic cells with antigen presented promotes antigen-specific CD8⁺ T cell proliferation and homing to inflammation site. These infiltrated CD8⁺ T cells released inflammatory cytokines including interferon γ (IFN-γ), tumor necrosis factor-α (TNF), transforming growth factor β (TGF-β) and transcription factor of tonicity-responsive enhancer-binding protein (TonEBP). These cytokines promotes macrophages and proximal tubular epithelial cells to express several factors including VEGF-C and VEGF-D that eventually further prompt kidney lymphangiogenesis. b. Constant inflammation microenvironment results in abnormally-structured lymphangiogenesis, which aggravates inflammation response in kidney. c. Immune regulation role of lymphangiogenesis functions differently in multiple pathological conditions, resulting in diverse immune microenvironments. In kidney fibrosis, reductions of B cells, Treg cells, IFN-γ-producing CD8⁺ T cells and CD11c⁺CD8⁺ T cells are shown. And in acute kidney injury, accumulations of Treg cells (Th17 cells) and local CD8⁺ T cells are inhibited. Of note, despite actively regulating immune cell migrations, during inflammation, infiltrated CD8⁺ T cells released IFN-γ, inducing PD-L1 expression by LECs, further inhibiting local CD8⁺ T cell effector function, reducing accumulation of local CD8⁺ T cell and alleviating kidney damage and progression of kidney fibrosis. Lymphangiogenesis significantly aids to this mechanism through enhanced immune cell trafficking. d. Lymphangiogenesis promote clearance of cellular debris, pro-inflammatory cytokines. In AKI, it significantly reduce the level of TGF-β to suppress the inflammatory response in kidney