MFG-E8 accelerates wound healing in diabetes by regulating "NLRP3 inflammasome-neutrophil extracellular traps" axis
MFG-E8 accelerates wound healing in diabetes by regulating "NLRP3 inflammasome-neutrophil extracellular traps" axis
复制标题
MFG-E8 通过调节“NLRP3 炎性体-中性粒细胞胞外陷阱”轴加速糖尿病伤口愈合
DOI：
10.1038/s41420-020-00318-7
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发表时间：
2020-09-10
影响因子：
7
通讯作者：
Zhang, Dongxin
中科院分区：
文献类型：
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作者：
Huang, Wei;Jiao, Jinyu;Zhang, Dongxin
NLRP3炎性体的持续激活和中性粒细胞外陷阱的释放（NETS）损害了糖尿病足溃疡（DFUS）的伤口愈合。我们先前的研究报告说，牛奶脂肪球表皮生长因子VIII（MFG-E8）减轻了全身性红斑狼疮的组织损伤。然而，MFG-E8对糖尿病伤口愈合的“ NLRP3炎性网络”炎症环的功能作用尚未完全阐明。在这项研究中，来自DFU患者的中性粒细胞容易患Netosis，释放更多的网。与健康对照组或糖尿病患者相比，DFU患者的净成分中性粒细胞弹性酶和蛋白酶3和炎性细胞因子IL-1β和IL-18的水平显着升高，尽管DFU患者的MFG-E8水平较高。 INMFGE8（ - / - ）糖尿病小鼠，皮肤伤口表现出夸张的炎症反应，包括白细胞浸润，NLRP3炎性体的过度激活（释放较高的IL-1β，IL-18和TNF-Alpha），很大程度上会导致较差的网状网络和较差的血管生成。当用高剂量葡萄糖或IL-18刺激时，MFG-E8缺乏的中性粒细胞释放出比WT中性粒细胞更多的网。给予重组MFG-E8后，WT ORMFGE8（ - / - ）中性粒细胞的IL-18-primed Netosis被显着抑制。此外，NET和MCRAMP（NET的组成部分，人类在人类中的鼠类cathelicidin ll-37等效）介导的NLRP3炎性体的激活以及IL-1β/IL-18的产生显着升高，与WT摩托噬细胞显着升高，与WT Mocrophages相比，与WT Mocrophages相比，该巨噬细胞也显着地升高了D.-distrativations vistanciond candivation in candivation indmentys dymfrend ramem。因此，我们的研究表明，作为“ NLRP3炎性网络”的抑制剂，外源性RMFG-E8炎症环的抑制剂可改善血管生成并加速伤口愈合，突出了DFU的可能治疗潜力。
Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on "NLRP3 inflammasome-NETs" inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1 beta and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. InMfge8(-/-)diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1 beta, IL-18, and TNF-alpha), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT orMfge8(-/-)neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1 beta/IL-18 were significantly elevated inMfge8(-/-)macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the "NLRP3 inflammasome-NETs" inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.