Neuropilin-2 contributes to LPS-induced corneal inflammatory lymphangiogenesis.
Neuropilin-2 (NP2), a high-affinity kinase-deficient co-receptor for vascular endothelial growth factor (VEGF)-C, is involved in embryonic vessel development, tumor growth, tumor lymphangiogenesis and metastasis. However, the pathological role of NP2 in other disorders, particularly under inflammatory lymphangiogenic conditions, remains largely unknown. In this study, we investigated the role of NP2 in inflammation-induced lymphangiogenesis in vivo using a lipopolysaccharide (LPS)-induced corneal neovascularization mouse model and in vitro using a macrophage-mouse lymphatic endothelial cell (mLEC) co-culture system. In the mouse model of LPS-induced inflammatory corneal neovascularization, NP2 and VEGFR-3 expression were rapidly up-regulated after LPS stimulation, and microRNA-mediated knockdown of NP2 significantly inhibited the up-regulation of VEGFR-3. Moreover, NP2 knockdown specifically inhibited the increase in the number of corneal lymphatic vessels but did not influence the increase in the number of blood vessels or macrophage recruitment induced by LPS. In a macrophage-LEC co-culture system, LPS up-regulated VEGFR-3 expression and induced mLEC migration and proliferation, and NP2 knockdown inhibited the up-regulation of VEGFR-3 expression and mLEC migration but not proliferation. Taken together, these results suggested that NP2 might be involved in the regulation of lymphangiogenesis via the regulation of VEGFR-3 expression during corneal inflammation. Therefore, NP2-targeted therapy might be a promising strategy for selective inhibition of inflammatory lymphangiogenesis in corneal inflammatory diseases, transplant immunology and oncology.
Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
Xianling
X
Tang
Department of Cardiovascular Medicine, First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
Junfeng
J
Sun
Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
Lingling
L
Du
Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
Haitao
H
Du
Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
Liyuan
L
Wang
Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, PR China.
Jieying
J
Mai
Department of Microbiology, Heilongjiang Province Key Laboratory for Immunity and Infection, Harbin Medical University, Harbin, PR China.
Fengmin
F
Zhang
Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, PR China. Electronic address: pingliu53@126.com.
Ping
P
Liu
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D018920:Coculture Techniques; D016510:Corneal Neovascularization / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D020868:Gene Silencing; D005822:Genetic Vectors; D007634:Keratitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D039943:Neuropilin-2 / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
D008070:Lipopolysaccharides; D035683:MicroRNAs; D039943:Neuropilin-2; D040321:Vascular Endothelial Growth Factor Receptor-3
Cornea; Inflammatory neovascularization; Lymphangiogenesis; Lymphatic endothelial cells; Neuropilin-2