AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes.
AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes.
复制标题
糖尿病患者中 AGE 诱导的自噬通过刺激巨噬细胞极化为 M1 来损害皮肤伤口愈合
DOI：
10.1038/srep36416
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发表时间：
2016-11-02
影响因子：
4.6
通讯作者：
Yao M
中科院分区：
文献类型：
--
作者：
Guo Y;Lin C;Xu P;Wu S;Fu X;Xia W;Yao M
自噬在生理和病理过程中是必不可少的，然而，自噬在皮肤创伤愈合中的作用及其分子机制仍不清楚。我们假设自噬在调节伤口愈合中起重要作用。在这里，我们表明增强的自噬对正常的皮肤愈合过程产生负面影响，并且与慢性伤口有关，如糖尿病小鼠皮肤或患者慢性伤口中增加的LC 3所证明的。此外，通过3-MA抑制自噬恢复了C57 BL/6或db/db小鼠的延迟愈合，表明自噬参与调节伤口愈合。此外，我们确定巨噬细胞是伤口中经历自噬的主要细胞类型，并且增加的自噬诱导巨噬细胞极化成M1，同时升高的CD 11 c群体和促炎细胞因子的基因表达。为了探索自噬损伤伤口愈合的潜在机制，我们测试了自噬调节剂IRF 8在自噬调节的巨噬细胞极化中的作用。在AGEs（晚期糖基化终产物）处理后，IRF 8激活上调巨噬细胞的自噬和M1极化，用shIRF 8阻断IRF 8抑制自噬活性和M1极化。总之，本研究阐明了AGEs诱导自噬并通过IRF 8激活调节巨噬细胞极化至M1，从而损害皮肤伤口愈合。
Autophagy is essential in physiological and pathological processes, however, the role of autophagy in cutaneous wound healing and the underlying molecular mechanism remain elusive. We hypothesized that autophagy plays an important role in regulating wound healing. Here, we show that enhanced autophagy negatively impacts on normal cutaneous healing process and is related to chronic wounds as demonstrated by the increased LC3 in diabetic mice skin or patients’ chronic wounds. In addition, inhibition of autophagy by 3-MA restores delayed healing in C57BL/6 or db/db mice, demonstrating that autophagy is involved in regulating wound healing. Furthermore, we identify that macrophage is a major cell type underwent autophagy in wounds and increased autophagy induces macrophages polarization into M1 with elevated CD11c population and gene expressions of proinflammatory cytokines. To explore the mechanism underlying autophagy-impaired wound healing, we tested the role of IRF8, a regulator of autophagy, in autophagy-modulated macrophages polarization. IRF8 activation is up-regulating autophagy and M1 polarization of macrophages after AGEs (advanced glycation endproducts) treatment, blocking the IRF8 with shIRF8 inhibits autophagic activity and M1 polarization. In summary, this study elucidates that AGEs induces autophagy and modulates macrophage polarization to M1 via IRF8 activation in impairment of cutaneous wound healing.
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DOI：
10.4049/jimmunol.1402277
发表时间：
2015-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abdel Fattah E;Bhattacharya A;Herron A;Safdar Z;Eissa NT
通讯作者：
Eissa NT
影响因子：
9.3
作者：
Hou X;Hu Z;Xu H;Xu J;Zhang S;Zhong Y;He X;Wang N
通讯作者：
Wang N
影响因子：
4.3
作者：
Arora, S;Pomposelli, F;Veves, A
通讯作者：
Veves, A
影响因子：
13.3
作者：
Cabrera, Sandra;Fernandez, Alvaro F.;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T