The immune regulatory role of lymphangiogenesis in kidney disease

Abstract

The renal lymphatic system is critical for maintaining kidney homeostasis and regulating the immune response inside the kidney. In various kidney pathological situations, the renal lymphatic network experiences lymphangiogenesis, which is defined as the creation of new lymphatic vessels. Kidney lymphangiogenesis controls immunological response inside the kidney by controlling lymphatic flow, immune cell trafficking, and immune cell regulation. Ongoing study reveals lymphangiogenesis's different architecture and functions in numerous tissues and organs. New research suggests that lymphangiogenesis in kidney disorders may regulate the renal immune response in various ways. The flexibility of lymphatic endothelial cells (LECs) improves the kidney's immunological regulatory function of lymphangiogenesis. Furthermore, current research has shown disparate findings regarding its impact on distinct renal diseases, resulting in contradictory outcomes even within the same kidney condition. The fundamental causes of the various effects of lymphangiogenesis on renal disorders remain unknown. In this thorough review, we explore the dual impacts of renal lymphangiogenesis on several kidney pathologies, with a particular emphasis on existing empirical data and new developments in understanding its immunological regulatory function in kidney disease. An improved understanding of the immunological regulatory function of lymphangiogenesis in kidney diseases might help design novel medicines targeting lymphatics to treat kidney pathologies.

Keywords: Immune cell trafficking; Immune regulation; Kidney disease; Kidney lymphangiogenesis; Lymphatic endothelial cell.

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

Fig. 2

Distinct mechanisms of lymphangiogenesis in certain kidney disease. a. In kidney hypertensive disease, sodium retention induces lymphangiogenesis through a Na +—TonEBP—VEGF-C pathway. Na + directly activates transcription factor of tonicity responsive enhancer-binding protein (TonEBP) in macrophages and dendritic cells (DCs) to promote expression of VEGF-C from macrophages, and then induces lymphangiogenesis. Sodium retention can directly activate DCs to express cytokines for further antigen-specific T cell accumulation and activation. Na + enters dendritic cells, subsequently leading to Ca2 + influx and then activation of protein kinase C, eventually resulting in increased expression of reactive oxygen species (ROS). ROS oxidates fatty acids into isolevuglandins (IsoLGs), which activates dendritic cells to produce proinflammatory cytokines (IL-1β, IL-6, IL-23) and activate T cells to proliferate and express inflammatory cytokines including TNF, IFN-γ and TGF-β. Lymphangiogenesis can reduce sodium retention, therefore inhibits DCs activation and the inflammatory response. b. In diabetic kidney disease, excessive cytokines expressed during the chronic inflammation condition create a specific microenvironment, which significantly induces abnormally-structured lymphangiogenesis