Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation

Abstract

Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-κB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-κB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-κB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-κB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTα and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTα and lymphotoxin β receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs.

Lymphotoxin‐α promotes tumor angiogenesis in HNSCC by modulating glycolysis in a PFKFB3‐dependent manner

“…Moreover, a pervious study reported the impaired lymphatic vessels formation in the LT‐α −/− mice, revealing the importance of LT‐α during lymphangiogenesis . And our previous research also suggested that LT‐α might promote lymphatic vessel formation in lymphatic malformation . LT‐α is a strong chemokine for the recruitment of immune cells, including B cells, CD4 T cells and dendritic cells .…”

“…The immunofluorescence and IHC were performed in accordance with our previous procedures. 16 Briefly, the tissue sections of formalin-fixed and paraffin-embedded tissues were dewaxed in xylene, rehydrated in ethanol and double-distilled water. Then, the antigen was retrieved through high pressure before immunostaining.…”

“…15 And our previous research also suggested that LT-α might promote lymphatic vessel formation in lymphatic malformation. 16 LT-α is a strong chemokine for the recruitment of immune cells, including B cells, CD4 T cells and dendritic cells. 17 These infiltrated immune cells further secrete pro-angiogenic factors and enhance tumor angiogenesis and lymphangiogenesis.…”

Recent Progress in Lymphangioma

“…LTs may accelerate the progression of LM by increasing the proliferation of LECs. LTs and LIGHT promote the development of LM by activating the NF-kB pathway to enhance LEC proliferation ( 75 ). The expression of LTs and their receptors was enhanced in LM, demonstrating the important role of LT signaling pathways in the pathogenesis of LM.…”

Pyruvate Kinase M2 Mediates Glycolysis in the Lymphatic Endothelial Cells and Promotes the Progression of Lymphatic Malformations

“…8 The findings from previous studies support the involvement of abnormal proliferation of LECs and lymphangiogenesis in the pathogenesis of LMs. 8,9 Despite abundant evidence regarding the association between PKM2-mediated glycolysis and rapidly proliferating disease, few studies have determined its significance in LMs. Therefore, in the present study, the role of PKM2 in LECs and lymphangiogenesis, as well as its potential effect in LMs, were investigated.…”