Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor.
Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor.
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DOI：
10.1038/srep09410
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发表时间：
2015-03-23
影响因子：
4.6
通讯作者：
Hirsch E
中科院分区：
文献类型：
--
作者：
Agrawal V;Jaiswal MK;Mallers T;Katara GK;Gilman-Sachs A;Beaman KD;Hirsch E
细胞器和蛋白质通过自噬被降解和循环，在这个过程中，被称为自噬的囊泡与溶酶体融合。自噬改变发生在各种疾病中，但它在早产(PTL)中的作用尚不清楚。与对照组相比，我们研究了自噬通量在两种PTL小鼠模型中的作用：1)炎症诱导的PTL(IPTL)，由Toll样受体激动剂诱导；2)非炎症(激素)诱导的PTL(NIPTL)。我们证明了自噬相关基因Atg4c和ATG7(参与微管相关蛋白1轻链3(LC3)B-I到自噬小体相关形式的脂化，LC3B-II)在IPTL期间在子宫和胎盘中显著减少，但在NIPTL中没有。IPTL的自噬通量发生改变，表现为LC3B类似物的积累和溶酶体相关膜蛋白(LAMP)-1、LAMP-2和V-ATPase的a2亚型(a2V，一种参与溶酶体酸化的酶)的减少。自噬的这些变化与子宫和胎盘中的NF-κB和促炎细胞因子/趋化因子的激活增加有关。在暴露于TLR配体的巨噬细胞中也可以看到类似的变化，并且阻断a2V可以增强这种变化。这些新的发现是IPTL自噬通量改变与高炎症和分娩之间存在关联的第一个证据。
Cellular organelles and proteins are degraded and recycled through autophagy, a process during which vesicles known as autophagosomes fuse with lysosomes. Altered autophagy occurs in various diseases, but its role in preterm labor (PTL) is unknown. We investigated the role of autophagic flux in two mouse models of PTL compared to controls: 1) inflammation-induced PTL (IPTL), induced by toll-like receptor agonists; and 2) non-inflammation (hormonally)-induced PTL (NIPTL). We demonstrate that the autophagy related genes Atg4c and Atg7 (involved in the lipidation of microtubule-associated protein 1 light chain 3 (LC3) B-I to the autophagosome-associated form, LC3B-II) decrease significantly in uterus and placenta during IPTL but not NIPTL. Autophagic flux is altered in IPTL, as shown by the accumulation of LC3B paralogues and diminishment of lysosome associated membrane protein (LAMP)-1, LAMP-2 and the a2 isoform of V-ATPase (a2V, an enzyme involved in lysosome acidification). These alterations in autophagy are associated with increased activation of NF-κB and proinflammatory cytokines/chemokines in both uterus and placenta. Similar changes are seen in macrophages exposed to TLR ligands and are enhanced with blockade of a2V. These novel findings represent the first evidence of an association between altered autophagic flux and hyper-inflammation and labor in IPTL.
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影响因子：
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作者：
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通讯作者：
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