摘要
It has been reported that neutrophil extracellular traps(NETs)impair wound healing in diabetes and that inhibiting NET generation(NETosis)improves wound healing in diabetic mice.Gonadotropin-releasing hormone(GnRH)agonists are associated with a greater risk of diabetes.However,the role of GnRH in diabetic wound healing is unclear.We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing.A mouse model of diabetes was established using five injections with streptozotocin.Mice with blood glucose levels>250 mg/dL were then used in the experiments.GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice.In contrast,GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing.The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients.In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate(PMA)-induced NETosis in mouse and human neutrophils.Furthermore,GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis,which were increased by GnRH treatment.These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds.Thus,inhibition of GnRH might be a novel treatment of diabetic foot ulcers.
基金
This study was supported by the National Research Foundation of Korea grant funded by the Korean government(MSIP)(No.2011-0030043(SRC)),(2017M3A9F7079339)
the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT,and Future Planning(2018R1A2B3009008).
