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Development of Inflammatory Hypoxia and Prevalence of Glycolytic Metabolism in Progressing Herpes Stromal Keratitis Lesions

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Development of Inflammatory Hypoxia and Prevalence of Glycolytic Metabolism in Progressing Herpes Stromal Keratitis Lesions Development of Inflammatory Hypoxia and Prevalence of Glycolytic Metabolism in Progressing Herpes Stromal Keratitis Lesions This information is current as Pushpa Rao and Susmit Suvas of September 24, 2021. J Immunol 2019; 202:514-526; Prepublished online 7 December 2018; doi: 10.4049/jimmunol.1800422 http://www.jimmunol.org/content/202/2/514 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/12/06/jimmunol.180042 Material 2.DCSupplemental References This article cites 56 articles, 15 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/202/2/514.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Development of Inflammatory Hypoxia and Prevalence of Glycolytic Metabolism in Progressing Herpes Stromal Keratitis Lesions Pushpa Rao* and Susmit Suvas*,† 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 ex- pression 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 Downloaded from neutrophils reduced the development of hypoxia in infected corneas. Additionally, in progressing HSK lesions, nuclear lo- calization of HIF-2a protein was detected in corneal epithelial cells, whereas HIF-1a protein stabilization was observed in infiltrating immune cells. Administration of acriflavine drug to HSV-1–infected mice inhibited nuclear accumulation of HIF-1a and HIF-2a 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 neovascula- http://www.jimmunol.org/ rization 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. The Journal of Immunology, 2019, 202: 514–526. erpes stromal keratitis (HSK) is a chronic inflammatory lesions, neutrophils are the most prominent immune cell type and condition that develops in the corneal tissue in response are considered essential for the development of HSK (7, 8). H to recurrent corneal HSV-1 infection. Studies carried out Outcomes of massive neutrophil influx are the development of in the mouse model of primary corneal HSV-1 infection have scarring, opacity, and angiogenesis (hem- and lymph-) in corneal shown the influx of monocytes, NK cells, macrophages, neutro- tissue, which affect the visual axis and ultimately cause the loss of by guest on September 24, 2021 phils, and T cells in inflamed corneal tissue (1). In the mouse vision (9, 10). model, HSK is broadly categorized into preclinical and clinical Neutrophils in an inflamed mucosal tissue have recently been disease periods (2). During the preclinical stage, viral replication shown to shape the development of inflammatory hypoxia (11, 12). in corneal lesions is regulated by innate sensors, such as type I Once developed, hypoxia results in the stabilization of hypoxia- IFN signaling, and by infiltrating innate immune cells like in- inducible factor (HIF) isoforms named HIF-1a and HIF-2a (13). flammatory monocytes and NK cells (3–6). Although the majority In a hypoxic microenvironment, HIF isoforms get complexed with of infectious virus is cleared from the infected cornea by six days HIF-1b protein to form a heterodimer. The latter migrates to the postinfection, the influx of leukocytes in the corneal stroma con- nucleus to induce the expression of a battery of genes that reg- tinues. Among the infiltrating leukocytes in progressing HSK ulate glycolytic metabolism, cell survival, cell differentiation, and angiogenesis (14, 15). In this study, we investigated the development of hypoxia, the *Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State Uni- expression of hypoxia-associated genes in HSV-1–infected corneas, † versity School of Medicine, Detroit, MI 48201; and Kresge Eye Institute, Detroit, and the outcome of blocking HIF dimerization on the severity of MI 48201 HSK. Our results showed an intense staining of pimonidazole hy- ORCIDs: 0000-0003-0176-0872 (P.R.); 0000-0002-8101-2710 (S.S.). drochloride, a chemical hypoxia marker, in the corneas with HSK. Received for publication March 22, 2018. Accepted for publication November 14, 2018. The magnitude of hypoxia positively correlated with the extent of neutrophil influx and the severity of HSK in infected corneas. This work was supported by National Eye Institute Grant EY022417 (to S.S.). Hypoxia in HSK-developing corneas was associated with nuclear Address correspondence and reprint requests to Dr. Susmit Suvas, 7223 Scott Hall, a a Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State Uni- localization of HIF-1 and HIF-2 protein and an elevated ex- versity School of Medicine, 540 E. Canfield, Detroit, MI 48201. E-mail address: pression of genes regulating glycolysis and the glucose/lactate [email protected] transporters. Interestingly, use of acriflavine (ACF) drug to block The online version of this article contains supplemental material. the nuclear translocation of HIF molecules caused an increased Abbreviations used in this article: ACF, acriflavine; CT, cycle threshold; EMT, influx of neutrophils but a decreased frequency of CD4 T cells and epithelial to mesenchymal transition; HIF, hypoxia-inducible factor; HK2, hexoki- nase 2; HSK, herpes stromal keratitis; PDK1, pyruvate dehydrogenase kinase 1; nongranulocytic myeloid cells in infected corneas. This resulted in PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PFKP, phospho- the development of reduced corneal hemangiogenesis but an in- fructokinase platelet; POI, post–ocular infection; PPP, pentose phosphate pathway; creased corneal opacity. Altogether, these findings suggest a po- qRT-PCR, quantitative RT-PCR; ROS, reactive oxygen species. tential contribution of hypoxia-associated genes in regulating the Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 pathogenesis of HSK. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800422 The Journal of Immunology 515 Materials and Methods Depletion of neutrophils Mice and corneal HSV-1 infection To deplete neutrophils, HSV-1–infected mice received i.p. injection of anti- Ly6G (clone 1A8; Bio X Cell) mAb. First, injection of mAb was given at Eight- to twelve-week-old female C57BL/6J (B6, stock no. 000664) mice m m from The Jackson Laboratory (Bar Harbor, ME) were used in all experi- the dose of 500 g/d/mouse. Subsequently, 250 g of anti-Ly6G mAb was ments. All experimental procedures were reviewed and approved by the given once a day to the treated group of infected mice. Isotype-matched Ab Institutional Animal Care and Use Committee of Wayne State University. was administered to a control group of infected mice. A total of five in- A cocktail of ketamine HCl (100 mg/ml) and xylazine HCl (20 mg/ml) jections were given starting from 7 through 11 d post–corneal infection. On solution was administered i.p. to anesthetize mice (20 g body weight), 12 d postinfection, mice received i.p. injection of pimonidazole hydro- prior to corneal HSV-1 infection. Development of HSK in C57BL/6J mice chloride and were euthanized to collect corneas and spleen tissue to was studied with HSV-1 (strain McKrae), and 1 3 105 PFU of virus was enumerate the frequency of neutrophils between both groups of infected applied only to the right cornea in 3 mlof13 PBS. To prevent any bac- mice by flow cytometry. terial superinfection, all mice were housed in microisolator cages with cage tops and were always handled under a Class II, Type A2 biosafety Immunofluorescence staining cabinet. Immunofluorescence staining to detect pimonidazole adducts, HIF-1a, a i.p. injection of Hypoxyprobe-1 HIF-2 , glucose transporter GLUT-1, GLUT-3, and monocarboxylate transporter MCT-4 protein was carried out on 8-mm-thick frozen corneal i.p. injection of pimonidazole hydrochloride (Hypoxyprobe-1 kit; sections. The frozen sections were fixed in 2% paraformaldehyde for 30 Natural Pharmacia International, Burlington, MA) was given to unin- min at room temperature prior to staining for pimonidazole and GLUT-1, fected and HSV-1–infected mice 4, 10, and 15 d postinfection. Mice -3, and MCT-4 protein. HIF staining was carried out on frozen sections that received pimonidazole drug at the concentration of 1.2 mg/20 g mouse were fixed in ice-cold acetone for 20 min at 220˚C. The immunofluo- body weight. The drug was dissolved in 0.9% normal saline. Ninety rescence staining procedure was carried out as described previously (16).
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