Table 1.

Molecular pathways regulating 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	[116, 117]
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	[125, 132]
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	[126, 127]
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	[134, 135]