IFN-λ Regulates Neutrophil Biology to Suppress Inflammation in Herpes Simplex Virus-1–Induced Corneal Immunopathology

Abstract

HSV-1 infection of the cornea causes a severe immunoinflammatory and vision-impairing condition called herpetic stromal keratitis (SK). The virus replication in corneal epithelium followed by neutrophil- and CD4+ T cell–mediated inflammation plays a dominant role in SK. Although previous studies demonstrate critical functions of type I IFNs (IFN-α/β) in HSV-1 infection, the role of recently discovered IFN-λ (type III IFN), specifically at the corneal mucosa, is poorly defined. Our study using a mouse model of SK pathogenesis shows that HSV-1 infection induces a robust IFN-λ response compared with type I IFN production at the corneal mucosal surface. However, the normal progression of SK indicates that the endogenous IFN responses are insufficient to suppress HSV-1–induced corneal pathology. Therefore, we examined the therapeutic efficacy of exogenous rIFN-λ during SK progression. Our results show that rIFN-λ therapy suppressed inflammatory cell infiltration in the cornea and significantly reduced the SK pathologic condition. Early rIFN-λ treatment significantly reduced neutrophil and macrophage infiltration, and IL-6, IL-1β, and CXCL-1 production in the cornea. Notably, the virucidal capacity of neutrophils and macrophages measured by reactive oxygen species generation was not affected. Similarly, ex vivo rIFN-λ treatment of HSV-1–stimulated bone marrow–derived neutrophils significantly promoted IFN-stimulated genes without affecting reactive oxygen species production. Collectively, our data demonstrate that exogenous topical rIFN-λ treatment during the development and progression of SK could represent a novel therapeutic approach to control HSV-1–induced inflammation and associated vision impairment.

Detecting free radicals post viral infections

“…Fluorescence spectrometers [88,89], flow cytometry [78,[90][91][92], and fluorescence microscopy [93] are normally used to read out of the fluorescent signals of optical probes. Fluorescence imaging offers higher spatial resolution and is sensitive and less invasive compared to other approaches.…”

Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis

“…The recurrent HSV-1 infection in the cornea leads to progressive corneal scarring, neovascularization, and damage to the sensory neurons that can result in neurotrophic keratopathy [ 17 , 19 , 20 ]. The lytic HSV-1 replication in epithelial cells activates host defense mechanisms primarily driven by the production of IFNs, chemokines, and cytokines [ 17 , 18 , 21 , 22 ]. These initial antiviral responses promote the infiltration and activation of innate immune cells (neutrophils, macrophages, natural killer (NK) cells, dendritic cells (DCs), and subsequently the induction of CD4 + and CD8 + T-cell-mediated adaptive immunity and antibody responses [ 18 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

“…These initial antiviral responses promote the infiltration and activation of innate immune cells (neutrophils, macrophages, natural killer (NK) cells, dendritic cells (DCs), and subsequently the induction of CD4 + and CD8 + T-cell-mediated adaptive immunity and antibody responses [ 18 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The innate type I and type III IFNs play a pivotal role in clearing the infection [ 21 , 22 , 30 , 31 ]. Type I IFNs are produced by all virus-infected nucleated cells, whereas type III IFNs are predominantly the product of virus-infected mucosal epithelial cells [ 21 , 22 , 32 , 33 , 34 ].…”

“…The innate type I and type III IFNs play a pivotal role in clearing the infection [ 21 , 22 , 30 , 31 ]. Type I IFNs are produced by all virus-infected nucleated cells, whereas type III IFNs are predominantly the product of virus-infected mucosal epithelial cells [ 21 , 22 , 32 , 33 , 34 ]. Although the induction of early innate IFN responses is essential for HSV-1 clearance, the subsequent uncontrolled activation of both innate and adaptive immune responses can cause irreversible damage to the cornea and lead to vision impairment [ 18 , 21 , 32 , 35 ].…”

“…Type I IFNs are produced by all virus-infected nucleated cells, whereas type III IFNs are predominantly the product of virus-infected mucosal epithelial cells [ 21 , 22 , 32 , 33 , 34 ]. Although the induction of early innate IFN responses is essential for HSV-1 clearance, the subsequent uncontrolled activation of both innate and adaptive immune responses can cause irreversible damage to the cornea and lead to vision impairment [ 18 , 21 , 32 , 35 ]. Innate IFNs not only participate in initial HSV-1 clearance but also function to regulate the induction of adaptive immune responses via several mechanisms still being investigated [ 8 , 21 , 22 , 32 , 36 ].…”