High Mobility Group Box-1 Promotes Inflammation-Induced Lymphangiogenesis via Toll-Like Receptor 4-Dependent Signalling Pathway.
Lymphangiogenesis in inflammation has received considerable attention in recent years. Administration of modulating lymphangiogenesis provides more possibilities of treating inflammation-associated diseases. However, the main mediators and factors governing inflammation-induced lymphangiogenesis (ILA) are yet to be defined. Here, we explored the role of HMGB1-TLR4 signalling pathway in modulating inflammation-induced lymphangiogenesis and its underlying mechanisms using an ILA mouse model and 2 cell lines. Our results show that HMGB1 promoted VEGF-C-induced HDLECs proliferation in a dose-dependent manner and TLR4 mediates HMGB1-induced LECs proliferation and tube formation in vitro. And in vivo, rHMGB1 treatment significantly promoted ILA, and the promoting effects was inhibited notably when HMGB1-TLR4 was blocked. HMGB1-associated ILA is primarily dependent on TLR4 but not on TLR2. In mechanisms, the recruitment and activation of CD11b+ cells are important cellular mechanisms in HMGB1-TLR4 associated ILA, and multiple key pro-lymphangiogenesis molecules mediates HMGB1-TLR4 associated ILA, including VEGF-C/VEGFR3, inflammatory factors IL-1β and TNF-α, MMP-2 and MMP-9 and NF-κB p65. In conclusion, HMGB1-associated ILA is primarily dependent on TLR4, and CD11b+ cells and multiple molecular mechanisms mediate HMGB1-TLR4 associated ILA. Furthermore, the ILA can be effectively modulated by HMGB1-TLR4 signalling. Consequently, administration of modulating ILA through HMGB1-TLR4 pathway may provide us more possibilities of treating inflammation and lymphangiogenesis associated diseases.
Tianjin Medical University Eye Hospital/Eye Institute, School of Optometry and Ophthalmology, Tianjin Medical University, Tianjin, China.|Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye institute, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
Longhui
L
Han
Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye institute, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
Minglian
M
Zhang
Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye institute, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
Mengmeng
M
Wang
Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye institute, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
Jinchen
J
Jia
Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye institute, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
Miying
M
Zhao
Hebei Provincial Key Laboratory of Ophthalmology, Hebei Provincial Eye institute, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
Yiming
Y
Fan
Tianjin Medical University Eye Hospital/Eye Institute, School of Optometry and Ophthalmology, Tianjin Medical University, Tianjin, China.
Xiaorong
X
Li
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000166:cytology; D015870:Gene Expression; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D042583:Lymphangiogenesis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
D024243:HMGB1 Protein; D053583:Interleukin-1beta; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D042582:Vascular Endothelial Growth Factor C