Human cathelicidin antimicrobial peptide LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK
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ORIGINAL ARTICLE
Human cathelicidin antimicrobial peptide LL‑37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK and Akt signaling pathways Takahiro Yanagisawa1 · Masakazu Ishii1 · Manami Takahashi1 · Kei Fujishima1,2 · Masahiro Nishimura1 Received: 19 March 2020 / Accepted: 25 August 2020 © Springer Nature B.V. 2020
Abstract LL-37, the only member of the cathelicidin family of cationic antimicrobial peptides in humans has been shown to exhibit a wide variety of biological actions in addition to its antimicrobial activity. However, the lymphangiogenic effect of LL-37 has not been elucidated yet. In this study, we examined the effects of LL-37 on lymphangiogenesis and evaluated the underlying molecular mechanisms. LL-37 treatment significantly increased the migration and tube-like formation of human dermal lymphatic microvascular endothelial cells (HDLECs) and promoted the expression of lymphangiogenic factor in HDLECs. Treatment with LL-37 increased phosphorylation of ERK and Akt proteins in HDLECs, and pretreatment with ERK and Akt inhibitors significantly blocked the LL-37-induced HDLEC migration and tube-like formation. Furthermore, to investigate the involvement of formyl peptide receptor-like 1 (FPRL1) signaling in LL-37-induced lymphangiogenesis, HDLECs were treated with an FPRL1 antagonist. Pretreatment with the FPRL1 antagonist inhibited LL-37-induced phosphorylation of ERK and Akt proteins and attenuated LL-37-induced HDLEC migration and tube-like formation. These data indicated that LL-37 induces lymphangiogenesis in lymphatic endothelial cells via FPRL1, and the activation of the ERK and Aktdependent signaling pathways. Keywords LL-37 · Lymphangiogenesis · ERK · Akt · FPRL1
Introduction The extraction of a tooth initiates a series of repair processes involving both soft and hard tissues. Delayed wound healing of the socket after tooth extraction is likely to cause postoperative infection. Wound healing is a complex physiological process involving hemostasis, inflammation, proliferation, and maturation [1]. Recently, the importance of lymphatic vessel formation in wound healing has also been reported [2]. The lymphatic system is crucial for the immune barrier function and tissue fluid balance [3]. During inflammation, * Masakazu Ishii [email protected]‑u.ac.jp 1
Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Science, 8‑35‑1 Sakuragaoka, Kagoshima 890‑8544, Japan
Department of Preventive Dentistry, Kagoshima University Graduate School of Medical and Dental Sciences, 8‑35‑1 Sakuragaoka, Kagoshima 890‑8544, Japan
2
lymphangiogenesis takes place to enhance the transport of filtered fluid, proteins, and immune cells [3]. A previous study indicated that parathyroid hormone (PTH) increased bone formation and promoted blood and lymphatic vessel formation in wound healing after tooth extraction [4]. Therefore, the regulation of lymphangiogenesis may also be important for improving wound healing after tooth
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