Mice Transgenic for IL-1 Receptor Antagonist Protein Are Resistant to Herpetic Stromal Keratitis: Possible Role for IL-1 in Herpetic Stromal Keratitis Pathogenesis

Abstract

Ocular infection with HSV may result in the blinding immunoinflammatory lesion stromal keratitis (SK). This represents a CD4+ T cell-mediated immunopathologic lesion in both humans and a mouse model. Early events in the pathogenesis that set the stage for SK are poorly understood. The present study evaluates the role of IL-1 using a transgenic mouse that overexpresses the IL-1 receptor antagonist (IL-1ra) protein. Such transgenic mice were markedly resistant to SK compared with IL-1ra−/− and C57BL/6 control animals. The resistance was shown to be the consequence of reduced expression of molecules such as IL-6, macrophage-inflammatory protein-2, and vascular endothelial growth factor, normally up-regulated directly or indirectly by IL-1. A critical event impaired in IL-1ra transgenic mice was vascular endothelial growth factor production with a consequent marked reduction in angiogenesis, an essential step in SK pathogenesis. Targeting IL-1 could prove to be a worthwhile therapeutic approach to control SK, an important cause of human blindness.

Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

“…By contrast, there was no obvious disease in the vast majority of mice infected with US9 Ϫ HSV and there was mild disease in 1 animal in the group of 15. Therefore, in agreement with previous studies (26), periocular skin infection requires spread from sensory neurons. Moreover, these observations further substantiate our conclusion that US9 is required for return from sensory ganglia to the periphery.…”

“…To ascertain whether US9 Ϫ HSV could cause keratitis, mice were infected in the cornea and HSK was followed over the course of 15 days (26). US9 Ϫ HSV caused HSK similar or identical to that produced by WT and US9 Ϫ R HSV; in all animals there was a striking inflammatory response characterized by neovascularization, significant cell influx (histopathology picture not shown), edema, necrosis, and ulceration (Fig.…”

“…4). The disease was scored (by an observer who was unaware of the treatment) in groups of 15 mice, as described (26). As shown in Fig.…”

“…retinal pigmented epithelial cells were infected with low doses of HSV-1, and plaques were stained for HSV antigens as described (24). BALB͞c mice were infected on the cornea by corneal scarification as described (25,26). Animals were killed after 2 days, eyes were removed, and corneas were dissected.…”

“…BALB͞c mice were infected with HSV by corneal scarification using 5 ϫ 10 4 or 5 ϫ 10 3 pfu, and HSK or periocular skin disease was scored daily between 2 and 15 days by an observer who was unaware of the virus groups and in some cases by using a slit lamp biomicroscope or photographed as described (18,26).…”