Seo Y, Ji Y W, Lee S M, Shim J, Noh H, Yeo A, Park C, Park M S, Chang E J, Lee H K
Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
1] Schephens Eye Research Institute, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do, Korea.
Cell Death Dis. 2014 Jun 26;5(6):e1309. doi: 10.1038/cddis.2014.260.
The pathogenesis of immune-mediated lacrimal gland (LG) dysfunction in Sjögren's syndrome has been thoroughly studied. However, the majority of dry eye (DE) is not related to Sjögren type, and its pathophysiology remains unclear. The purpose of this study was to determine and investigate the protective mechanisms against DE stress in mice. DE induced prominent blood vessel loss without apoptosis or necrosis in the LG. Autophagic vacuoles, distressed mitochondria, and stressed endoplasmic reticulum were observed via electron microscopy. Immunoblotting confirmed the increase in autophagic markers. Glycolytic activities were enhanced with increasing levels of succinate and malate that, in turn, activated hypoxia-inducible factor (HIF)-1α. Interestingly, the areas of stable HIF-1α expression overlapped with COX-2 and MMP-9 upregulation in LGs of DE-induced mice. We generated HIF-1α conditional knockout (CKO) mice in which HIF-1α expression was lost in the LG. Surprisingly, normal LG polarities and morphologies were completely lost with DE induction, and tremendous acinar cell apoptosis was observed. Similar to Sjögren's syndrome, CD3(+) and CD11b(+) cells infiltrated HIF-1α CKO LGs. Our results show that DE induced the expression of HIF-1α that activated autophagy signals to prevent further acinar cell damage and to maintain normal LG function.
干燥综合征中免疫介导的泪腺（LG）功能障碍的发病机制已得到深入研究。然而，大多数干眼症（DE）与干燥综合征类型无关，其病理生理学仍不清楚。本研究的目的是确定并研究小鼠中针对DE应激的保护机制。DE诱导LG中显著的血管丧失，但无细胞凋亡或坏死。通过电子显微镜观察到自噬泡、受损的线粒体和应激的内质网。免疫印迹证实自噬标志物增加。糖酵解活性随着琥珀酸和苹果酸水平的增加而增强，进而激活缺氧诱导因子（HIF）-1α。有趣的是，在DE诱导的小鼠LG中，稳定的HIF-1α表达区域与COX-2和MMP-9上调区域重叠。我们构建了HIF-1α条件性敲除（CKO）小鼠，其中LG中HIF-1α表达缺失。令人惊讶的是，DE诱导后，正常的LG极性和形态完全丧失，观察到大量腺泡细胞凋亡。与干燥综合征相似，CD3(+)和CD11b(+)细胞浸润HIF-1α CKO LG。我们的结果表明，DE诱导HIF-1α表达，激活自噬信号，以防止腺泡细胞进一步损伤并维持LG正常功能。
