IL-27 modulates macrophage immunometabolism to promote dual anti-viral and anti-inflammatory effector functions during ocular HSV-1 infection

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B572
Abstract ID: 4577

Presenting Author:
Gurjinder Kaur , Graduate Research Assistant at Auburn University College of Veterinary Medicine

Abstract:

Herpetic stromal keratitis (HSK) is a painful and vision-impairing disease caused by recurrent HSV-1 infection of the cornea. The macrophages play a central role in HSV-1 clearance in the cornea through phagocytosis of infected epithelial cells and apoptotic neutrophils. However, whether HSV-1 modulates macrophage immunometabolism to evade anti-viral immunity is unknown. Our study shows that HSV-1 infection dysregulates mitochondrial metabolisms in macrophages with increased immune-responsive gene 1 (Irg1) expression. Our results indicate that the HSV-1-induced Irg1/itaconate axis suppresses IFN-β production by macrophages. Conversely, our data suggest that HSV-1 infection stimulates IL-27 production by macrophages. Using a primary corneal HSV-1 infection mouse model and IL-27 receptor knockout mice, we show that IL-27 plays a critical role in controlling HSV-1 shedding from the cornea, the optimum induction of effector CD4⁺ T cell responses, and limiting HSK progression. Using in vitro bone marrow-derived macrophages, we show that IL-27 suppresses HSV-1-induced Irg1 expression and plays an anti-viral role by regulating macrophage-mediated HSV-1 killing, IFN-β production, and IFN-stimulated genes expression after HSV-1 infection. Our results indicate that IL-27 promotes endogenous anti-viral and anti-inflammatory responses, and modulating IL-27-mediated metabolic programming in macrophages may represent a promising therapeutic approach to control HSK progression.