Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201; and.
Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201; and
J Immunol. 2019 Jan 15;202(2):514-526. doi: 10.4049/jimmunol.1800422. Epub 2018 Dec 7.
Chronic inflammation in tissues often causes the development of hypoxia. Herpes stromal keratitis (HSK) is a corneal chronic inflammatory condition that develops in response to recurrent HSV-1 infection. In this study, we investigated the development of hypoxia, the expression of hypoxia-associated glycolytic genes in HSV-1 infected corneas, and the outcome of blocking hypoxia-inducible factor (HIF) dimerization on the severity of HSK. Our results showed the development of hypoxia, an elevated expression of hypoxia-associated glycolytic genes, and an increased level of lactate in corneas with progressing HSK lesions. The magnitude of hypoxia correlated with the extent of neutrophils infiltrating the infected corneas, and the depletion of neutrophils reduced the development of hypoxia in infected corneas. Additionally, in progressing HSK lesions, nuclear localization of HIF-2α protein was detected in corneal epithelial cells, whereas HIF-1α protein stabilization was observed in infiltrating immune cells. Administration of acriflavine drug to HSV-1-infected mice inhibited nuclear accumulation of HIF-1α and HIF-2α protein in immune cell types and epithelial cells, respectively, in infected corneas. As a result, a decreased influx of CD4 T cells and nongranulocytic myeloid cells, but an increased influx of neutrophils, was noted in developing HSK lesions. Interestingly, acriflavine treatment given during the clinical disease period decreased neovascularization but increased the opacity in HSV-1-infected corneas. Taken together, the results of our study lay the foundation to dissect the role of inflammatory hypoxia and hypoxia-associated genes in the pathogenesis of HSK.
组织中的慢性炎症常导致缺氧的发生。单纯疱疹性基质角膜炎（HSK）是一种角膜慢性炎症性疾病，由复发性 HSV-1 感染引起。在这项研究中，我们研究了 HSV-1 感染角膜中缺氧的发展、与缺氧相关的糖酵解基因的表达以及阻断缺氧诱导因子（HIF）二聚化对 HSK 严重程度的影响。我们的结果表明，在进展性 HSK 病变中，出现了缺氧的发展、与缺氧相关的糖酵解基因的表达上调以及乳酸水平的升高。缺氧的程度与浸润感染角膜的中性粒细胞的数量相关，而中性粒细胞的耗竭减少了感染角膜中的缺氧发展。此外，在进展性 HSK 病变中，我们在角膜上皮细胞中检测到 HIF-2α 蛋白的核定位，而在浸润的免疫细胞中观察到 HIF-1α 蛋白的稳定。在 HSV-1 感染的小鼠中给予吖啶黄素药物，分别抑制了感染角膜中免疫细胞类型和上皮细胞中 HIF-1α 和 HIF-2α 蛋白的核积累。结果，在发展中的 HSK 病变中，观察到 CD4 T 细胞和非粒细胞性髓样细胞的流入减少，而中性粒细胞的流入增加。有趣的是，在 HSV-1 感染的角膜中，在临床疾病期给予吖啶黄素治疗可减少新生血管形成，但增加了混浊度。总之，我们研究的结果为研究炎症性缺氧和 HSK 发病机制中与缺氧相关的基因的作用奠定了基础。
