Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds.
Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds.
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作者：
Xu F;Othman B;Lim J;Batres A;Ponugoti B;Zhang C;Yi L;Liu J;Tian C;Hameedaldeen A;Alsadun S;Tarapore R;Graves DT
上皮再形成是粘膜创伤愈合的重要组成部分。令人惊讶的是，关于糖尿病对粘膜愈合的分子事件的影响知之甚少。我们研究了转录因子叉头盒O 1（Foxo 1）在糖尿病和正常血糖小鼠口腔伤口角质形成细胞特异性Foxo 1缺失中的作用。糖尿病粘膜伤口愈合明显延迟，细胞迁移和增殖减少。Foxo 1缺失挽救了糖尿病对愈合的负面影响，但在血糖正常的小鼠中产生了相反的效果。糖尿病在体内和体外高糖条件下以Foxo 1依赖性方式增强趋化因子（C-C基序）配体20（CCL 20）和白细胞介素-36 γ（IL-36γ）的表达。高糖刺激的Foxo 1与CCL 20和IL-36γ启动子的结合以及CCL 20和IL-36γ显著抑制了这些细胞在高糖条件下的迁移。在正常愈合中，Foxo 1是转化生长因子-β1（TGF-β1）表达所必需的，在标准葡萄糖条件下，TGF-β1在体外挽救了Foxo 1沉默对迁移的负面影响。我们认为，Foxo 1在糖尿病或高糖条件下通过促进高水平的CCL 20和IL-36γ表达而损害愈合，但在正常条件下，通过诱导TGF-β1而增强愈合。这一发现为Foxo 1如何介导糖尿病对粘膜伤口愈合的影响提供了机制上的见解。
Re-epithelialization is an important part in mucosal wound healing. Surprisingly little is known about the impact of diabetes on the molecular events of mucosal healing. We examined the role of the transcription factor forkhead box O1 (Foxo1) in oral wounds of diabetic and normoglycemic mice with keratinocyte-specific Foxo1 deletion. Diabetic mucosal wounds had significantly delayed healing with reduced cell migration and proliferation. Foxo1 deletion rescued the negative impact of diabetes on healing but had the opposite effect in normoglycemic mice. Diabetes in vivo and in high glucose conditions in vitro enhanced expression of chemokine (C-C motif) ligand 20 (CCL20) and interleukin-36γ (IL-36γ) in a Foxo1-dependent manner. High glucose–stimulated Foxo1 binding to CCL20 and IL-36γ promoters and CCL20 and IL-36γ significantly inhibited migration of these cells in high glucose conditions. In normal healing, Foxo1 was needed for transforming growth factor-β1 (TGF-β1) expression, and in standard glucose conditions, TGF-β1 rescued the negative effect of Foxo1 silencing on migration in vitro. We propose that Foxo1 under diabetic or high glucose conditions impairs healing by promoting high levels of CCL20 and IL-36γ expression but under normal conditions, enhances it by inducing TGF-β1. This finding provides mechanistic insight into how Foxo1 mediates the impact of diabetes on mucosal wound healing.
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DOI：
10.1083/jcb.201305074
发表时间：
2013-10-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ponugoti B;Xu F;Zhang C;Tian C;Pacios S;Graves DT
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DOI：
10.1038/jid.2009.65
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2009-09
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Ponugoti B;Dong G;Graves DT
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DOI：
10.4049/jimmunol.1003162
发表时间：
2011-02-15
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Journal of immunology (Baltimore, Md. : 1950)
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Johnston A;Xing X;Guzman AM;Riblett M;Loyd CM;Ward NL;Wohn C;Prens EP;Wang F;Maier LE;Kang S;Voorhees JJ;Elder JT;Gudjonsson JE
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DOI：
10.1165/rcmb.2009-0315oc
发表时间：
2011-02-01
影响因子：
6.4
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