Neurotrophic Keratitis

Semeraro, Francesco; Forbice, Eliana; Romano, Vito; Angi, Martina; Romano, Mario R.; Filippelli, Mariaelena; Iorio, Roberto; Costagliola, Ciro

doi:10.1159/000354380

Cited by 100 publications

(130 citation statements)

References 51 publications

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“…It is likely that initiation of consensual BR in the contralateral eyes of these patients is impaired, which could cause corneal desiccation that amplifies the severity and chronicity of virus-induced immunopathology in the infected eye. Indeed, dry eye and neurotrophic damage to the cornea can be associated with HSK in humans (34,35). Our studies demonstrate for the first time that corneal desiccation associated with total loss of corneal BR is a major contributing factor in the severe and chronic inflammation that develops in mice with HSK.…”

Section: Discussionmentioning

confidence: 65%

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

Yun

Rowe

Lathrop

et al. 2014

J Virol

108

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Herpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4 ؉ T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted. IMPORTANCEHSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4 ؉ T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease.

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Section: Discussionmentioning

confidence: 65%

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

Yun

Rowe

Lathrop

et al. 2014

J Virol

108

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“…In humans, it was observed that the impairment of corneal innervation can cause corneal ulcers (neurotrophic keratitis) [49]. Patients with neurotrophic keratitis present decreased corneal sensitivity with alterations in corneal epithelium, nerve, keratocyte, and endothelium.…”

Section: Discussionmentioning

confidence: 99%

In vitro 3D corneal tissue model with epithelium, stroma, and innervation

et al. 2017

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The interactions between corneal nerve, epithelium, and stroma are essential for maintaining a healthy cornea. Thus, corneal tissue models that more fully mimic the anatomy, mechanical properties and cellular components of corneal tissue would provide useful systems to study cellular interactions, corneal diseases and provide options for improved drug screening. Here a corneal tissue model was constructed to include the stroma, epithelium, and innervation. Thin silk protein film stacks served as the scaffolding to support the corneal epithelial and stromal layers, while a surrounding silk porous sponge supported neuronal growth. The neurons innervated the stromal and epithelial layers and improved function and viability of the tissues. An air-liquid interface environment of the corneal tissue was also mimicked in vitro, resulting in a positive impact on epithelial maturity. The inclusion of three cell types in co-culture at an air-liquid interface provides an important advance for the field of in vitro corneal tissue engineering, to permit improvements in the study of innervation and corneal tissue development, corneal disease, and tissue responses to environmental factors.

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“…Neurotrophic keratitis is a potentially blinding condition whose corneal pathology (cloudiness, erosions, dry surface, increased risk of infections) results from reduced innervation of the cornea by stromal and ICNs (Sacchetti and Lambiase, ; Semeraro et al, ; Shaheen et al, ). It occurs secondary to neuropathy of the trigeminal nerve or after ocular surgery, trauma, and/or viral infections.…”

Section: Sbn Loss Stops Corneal Epithelial Cell Proliferationmentioning

confidence: 99%

Corneal epithelial cells function as surrogate Schwann cells for their sensory nerves

Stepp

Tadvalkar

Hakh

et al. 2016

Glia

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The eye is innervated by neurons derived from both the central nervous system and peripheral nervous system. While much is known about retinal neurobiology and phototransduction, less attention has been paid to the innervation of the eye by the PNS and the roles it plays in maintaining a functioning visual system. The ophthalmic branch of the trigeminal ganglion contains somas of neurons that innervate the cornea. These nerves provide sensory functions for the cornea and are referred to as intraepithelial corneal nerves (ICNs) consisting of subbasal nerves and their associated intraepithelial nerve terminals. ICNs project for several millimeters within the corneal epithelium without Schwann cell support. Here, we present evidence for the hypothesis that corneal epithelial cells function as glial cells to support the ICNs. Much of the data supporting this hypothesis is derived from studies of corneal development and the reinnervation of the ICNs in the rodent and rabbit cornea after superficial wounds. Corneal epithelial cells activate in response to injury via mechanisms similar to those induced in Schwann cells during Wallarian Degeneration. Corneal epithelial cells phagocytize distal axon fragments within hours of ICN crush wounds. During aging, the proteins, lipids, and mitochondria within the ICNs become damaged in a process exacerbated by UV light. We propose that ICNs shed their aged and damaged termini and continuously elongate to maintain their density. Available evidence points to new unexpected roles for corneal epithelial cells functioning as surrogate Schwann cells for the ICNs during homeostasis and in response to injury.

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Neurotrophic Keratitis

Cited by 100 publications

References 51 publications

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

In vitro 3D corneal tissue model with epithelium, stroma, and innervation

Corneal epithelial cells function as surrogate Schwann cells for their sensory nerves

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