Effect of hydroxychloroquine and characterization of autophagy in a mouse model of endometriosis.
Effect of hydroxychloroquine and characterization of autophagy in a mouse model of endometriosis.
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DOI：
10.1038/cddis.2015.361
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发表时间：
2016-01-14
影响因子：
9
通讯作者：
Nanjundan M
中科院分区：
文献类型：
--
作者：
Ruiz A;Rockfield S;Taran N;Haller E;Engelman RW;Flores I;Panina-Bordignon P;Nanjundan M
在子宫内膜异位症中，脱落的子宫内膜细胞（通常发生失巢凋亡）的存活潜力增加被认为促进了病变的发展。可能改变失巢凋亡的一种机制是自噬。使用自噬通量抑制剂羟氯喹（HCQ），我们确定，它降低了人子宫内膜和子宫内膜T-HESC细胞的体外存活能力。我们还发现，HCQ可以减少病变数量和破坏病变组织病理学，以及增加腹腔巨噬细胞和IP-10（10 kDa干扰素-γ诱导蛋白）趋化因子在小鼠子宫内膜异位症模型。我们注意到，自噬标记物的一个子集的RNA水平降低病变相对于子宫角从子宫内膜异位症诱导（未处理）的小鼠。此外，自噬标记物的RNA水平降低，子宫角的子宫内膜异位症诱导的小鼠相比，从控制。然而，我们注意到，与对照组相比，LC 3B（微管相关蛋白1轻链3β;一种自噬标记物）在子宫角中的表达在子宫内膜异位症诱导小鼠的子宫角中增加。通过免疫组化染色的人类乳腺癌组织芯片，我们观察到LC 3B的表达主要是在上皮细胞相对于基质细胞在在位和异位子宫内膜。通过透射电子显微镜，与对照组的子宫角相比，子宫内膜异位诱导小鼠的子宫角细胞含有更多的脂滴（而不是自噬体）。总的来说，我们的研究结果表明，自噬途径是失调，在异位和在位子宫内膜异位症的小鼠模型，HCQ有潜力作为一种治疗剂的妇女患有子宫内膜异位症。
In endometriosis, the increased survival potential of shed endometrial cells (which normally undergo anoikis) is suggested to promote lesion development. One mechanism that may alter anoikis is autophagy. Using an autophagic flux inhibitor hydroxychloroquine (HCQ), we identified that it reduces the in vitro survival capacity of human endometriotic and endometrial T-HESC cells. We also identified that HCQ could decrease lesion numbers and disrupt lesion histopathology, as well as increase the levels of peritoneal macrophages and the IP-10 (10 kDa interferon-γ-induced protein) chemokine in a mouse model of endometriosis. We noted that RNA levels of a subset of autophagic markers were reduced in lesions relative to uterine horns from endometriosis-induced (untreated) mice. In addition, the RNA levels of autophagic markers were decreased in uterine horns of endometriosis-induced mice compared with those from controls. However, we noted that protein expression of LC3B (microtubule-associated protein 1 light-chain 3β; an autophagic marker) was increased in uterine horns of endometriosis-induced mice compared with uterine horns of controls. By immunohistochemical staining of a human endometriosis-focused tissue microarray, we observed LC3B expression predominantly in epithelial relative to stromal cells in both eutopic and ectopic endometria. Via transmission electron microscopy, cells from eutopic endometria of endometriosis-induced mice contained more lipid droplets (rather than autophagosomes) compared with uterine horns from controls. Collectively, our findings indicate that the autophagic pathway is dysregulated in both ectopic and eutopic endometrium in a murine model of endometriosis and that HCQ has potential as a therapeutic agent for women afflicted with endometriosis.