Table 1 Molecular pathways regulating lymphangiogenesis in inflammatory bowel disease
From: Cellular and molecular mediators of lymphangiogenesis in inflammatory bowel disease
Molecule(s) | Functions in the IBD | Mechanism | References |
|---|---|---|---|
CELC2 | Inhibits LEC-mediated lymphangiogenesis to cause a sustained inflammatory response in the IBD process | Activates platelets by interacting with the LECs surface ligand Podoplanin, to inhibit LECs-mediated lymphangiogenesis | [60] |
VEGF-C/VEGFR3 | Prevents chronic inflammation and promotes disease regression | Promotes in vitro proliferation, migration, and tissue formation of human intestinal LECs, ultimately leading to functional lymphangiogenesis which can alleviate IBD | [5] |
VEGF-A and VEGF-D | Promote lymphangiogenesis and decrease local inflammation | Neutrophils increase VEGF-A bioavailability and bioactivity via the secretion of MMP-9, heparinase, and to a lesser extent VEGF-D | [43] |
NF-ΚB | Result in inflammatory-induced lymphatic formation | NF-κB and Prox1 synergistic control of VEGFR3 expression lead to increased receptor availability, resulting in reduced local VEGF-C/D net availability to cause VEGFR3 signal deficiency, blocked lymphoid activation in IBD, and exacerbating the disease | |
TLR4 | Blocking TLR4 can reduce the formation of inflammatory lymphatic vessels and improve the enteritis phenotype induced by DSS | Highly expressed in LECs; it is the main regulating medium for LPS to activate NF-KB | |
TLR4- NF-κB/JNK pathways | Promotes human dermal lymphatic endothelial cells' (HDLECs') capacity of tube-like formation in vitro and accelerates lymphangiogenesis and lymph node metastasis in nude mice via LPS induction | LPS increases VEGF-C expression to promote cell motility and lymphangiogenesis through the TLR4- NF-κB/JNK signaling | [123] |
S1P | The concentration grade of S1P in lymph and carcinoma tissues affects lymphatic transport and lymphangiogenesis of cancer cells, thereby promoting inflammation progression and CAC metastasis | Through the S1P-STAT3-S1PR1 amplification ring, the lymphatic transport in inflammation is affected, thereby promoting the accumulation of pro-inflammatory factors such as IL-6 and TNF-α to aggravate the disease | |
Notch/DLL4 signaling | The genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression | The continuous regeneration and proliferation of lymphatic capillaries are mediated by Notch signaling and the expression of the Notch ligand delta-like 4 (DLL4) in lacteals which requires activation of VEGFR3 and VEGFR2 | [128] |
NRP-2 | Promote tumor cell migration, invasion, and lymph node metastasis | The activation of the VEGF-C/D-NRP-2 axis stimulates lymphatic sprouting, facilitates the extension of LEC growth leading edge, and promotes the polarization of LECs. This axis is also the foundation of the sprouting and formation of a new network of lymphatic vessels | [133] |
EMILIN-1/α9β1 | The downregulation of EMILIN-1 leads to an inhibited lymphangiogenesis and a blockage in the dissipation of inflammation | EMILIN1 interacts with integrin α9 in the lymphatic vasculature to promote lymphatic valve formation and maintenance and exhibits a modulatory function in the proliferation by acting as a "guiding" molecule in the migration of LECs |