Role of Insulin-Like Growth Factor Binding Protein-3 in the Pathogenesis of Herpes Stromal Keratitis

Abstract

The goal of this study was to determine the role of insulin-like growth factorbinding protein-3 (IGFBP-3) in the pathogenesis of herpes stromal keratitis (HSK). METHODS. In an unbiased approach, a membrane-based protein array was carried out to determine the level of expression of pro-and anti-angiogenic molecules in uninfected and HSV-1 infected corneas. Quantitative RT-PCR and ELISA assays were performed to measure the amounts of IGFBP-3 at mRNA and protein levels. Confocal microscopy documented the localization of IGFBP-3 in uninfected and infected corneal tissue. Flow cytometry assay showed the frequency of immune cell types in infected corneas from C57BL/6J (B6) and IGFBP-3 knockout (IGFBP-3 −/−) mice. Slit-lamp microscopy was used to quantitate the development of opacity and neovascularization in infected corneas from both groups of mice. RESULTS. Quantitation of protein array dot blot showed an increased level of IGFBP-3 protein in HSV-1 infected than uninfected corneas and was confirmed with ELISA and quantitative RT-PCR assays. Cytosolic and nuclear localization of IGFBP-3 were detected in the cells of corneal epithelium, whereas scattered IGFBP-3 staining was evident in the stroma of HSK developing corneas. Increased opacity and hemangiogenesis were noted in the corneas of IGFBP-3 −/− than B6 mice during the clinical period of HSK. Furthermore, an increased number of leukocytes comprising of neutrophils and CD4 T cells were found in HSK developing corneas of IGFBP-3 −/− than B6 mice. CONCLUSIONS. Our data showed that lack of IGFBP-3 exacerbates HSK, suggesting the protective effect of IGFBP-3 protein in regulating the severity of HSK.

Antiviral properties of placental growth factors: A novel therapeutic approach for COVID-19 treatment

“…Macrophages undergo oxidative phosphorylation and acquire anti-inflammatory properties( 128 ).IGF family plays an important immune function in inflammatory lung injury and may provide a therapeutic target for humans in response to COVID-19 outbreak.Last year, researchers demonstrated the inhibitory effect of IGF-1 on phagocytosis by alveolar epithelial cells, with enhanced phagocytic activity noted on IGF-1 blockade in asthmatic mice. This supports potential use of IGF-1 as a target in inflammatory pulmonary conditions( 129 ).…”

Pathogenesis of Herpes Stromal Keratitis: Immune Inflammatory Response Mediated by Inflammatory Regulators

“…In addition to the cytokines and chemokines required for inflammatory immune responses, this review also emphasizes the important role of glycoproteins, SP, HVEM, hypoxia, and microRNAs in HSK pathogenesis. We believe that more pathogenic factors will be found in future scientific work, such as insulin-like growth factor-binding protein-3, which is present in the epithelium and stroma of HSK developing corneas and protects from aggravation of the lesions (144). It is important to have more in-depth research on hypoxia, microRNA, SP, and other areas to find more effective therapeutic targets for HSK and reduce the blindness rate.…”

Loss of Osteopontin Expression Reduces HSV-1-Induced Corneal Opacity

“… 56 In terms of corneal HSV-1 infection and consistent with our data, a previous study reported that OPN-deficient mice presented with a significant drop in the incidence and severity of herpes stromal keratitis (HSK) following corneal infection out to day 15 pi. 57 Whereas several factors known to contribute to or correlate with opacity and HSK were evaluated after OPN neutralization, including IL-1α, IL-6, CXCL1, CCL2, MMPs, and IGFBP-3, 58 – 61 MMP-8 was the only factor investigated that changed (increased) following anti-OPN treatment. In general, MMPs are zinc-binding proteolytic enzymes that are involved in degradation and remodeling of the extracellular matrix in tissues, including the cornea.…”