Corneal nerves in health and disease

Al-Aqaba, Mouhamed; Dhillon, Virinder K; Mohammed, Imran; Said, Dalia G.; Dua, Harminder S.

doi:10.1016/j.preteyeres.2019.05.003

Cited by 207 publications

(184 citation statements)

References 293 publications

(348 reference statements)

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“…Corneal sensory nerves are vital for maintaining epithelial integrity [49]. It follows that corneal nerve dysfunction is the pathophysiologic basis of a variety of ocular surface diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies show that it can take several years for corneal nerves to completely regenerate after Table 2. Legend: DCN, decorin; Gel, fluid gel surgical-induced ablation [14,15,50], potentially leading to secondary ocular surface conditions, such as dry eye disease and neurotrophic keratopathy [17,49,51]. Despite the clinical importance of treatments to promote corneal nerve regeneration, there are relatively few therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

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The neuroregenerative effects of topical decorin on the injured mouse cornea

Downie

Grover

et al. 2020

J Neuroinflammation

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Background: The cornea is innervated with a rich supply of sensory nerves that play important roles in ocular surface health. Any injury or pathology of the corneal nerves increases the risk of dry eye disease and infection. This study aims to evaluate the therapeutic potential of topical decorin to improve corneal nerve regeneration in a mouse model of sterile epithelial abrasion injury. Methods: Bilateral central corneal epithelial abrasions (2-mm, Alger Brush) were performed on young C57BL/6 J mice to remove the corneal sensory nerves. Decorin, or vehicle, was applied topically, three times per day for 1 week or every 2 h for 6 h. Spectral-domain optical coherence tomography was performed to measure the abrasion area and corneal thickness. Wholemount immunofluorescence staining was used to assess sensory nerve regeneration (β-tubulin III) and immune cell density (CD45, Iba1, CD11c). To investigate the specific role of dendritic cells (DCs), Cx3cr1 gfp/gfp mice, which spontaneously lack resident corneal epithelial DCs, were also investigated. The effect of prophylactic topical administration of recombinant human decorin (applied prior to the abrasion) was also investigated. Nerve tracing (NeuronJ software) was performed to compare recovery of basal nerve axons and superficial nerve terminals in the central and peripheral cornea. Results: At 6 h after injury, topical decorin application was associated with greater intraepithelial DC recruitment but no change in re-epithelialisation or corneal thickness, compared to the vehicle control. One week after injury, sub-basal nerve plexus and superficial nerve terminal density were significantly higher in the central cornea in the decorin-treated eyes. The density of corneal stromal macrophages in the decorin-treated eyes and their contralateral eyes was significantly lower compared to saline-treated corneas. No significant improvement in corneal nerve regeneration was observed in Cx3cr1 gfp/gfp mice treated with decorin. Conclusions: Decorin promotes corneal epithelial nerve regeneration after injury. The neuroregenerative effect of topical decorin was associated with a higher corneal DC density during the acute phase, and fewer macrophages at the study endpoint. The corneal neuroregenerative effects of decorin were absent in mice lacking intraepithelial DCs. Together, these findings support a role for decorin in DC-mediated neuroregeneration following corneal abrasion injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The neuroregenerative effects of topical decorin on the injured mouse cornea

Downie

Grover

et al. 2020

J Neuroinflammation

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“…Corneal innervation is supplied by the ophthalmic branch of the trigeminal nerve. While corneal innervation is described in detail elsewhere and is beyond the scope of this review, it is important to note that the corneal epithelium is the highest innervated structure in the body due to the high density of intraepithelial nerve terminals ( Figure 1B) (4). This, along with the tight barrier function of the epithelium, plays a major role in protecting intraocular structures from the outside environment.…”

Section: Introductionmentioning

confidence: 99%

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

2020

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The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.

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“…As a summarizing term of constant wear and challenge, the term attrition has been even used in psychology as one of the processes of challenges potentially leading to a burnout [5]. In ophthalmology again, the term attrition has been used in association with structural abnormalities, such as nerves in neurotrophic keratopathy [6]. In the presented model, attrition summarizes all the effects of mechanical forces constantly and repeatedly challenging tissues at the ocular surfaces with friction, stretching and compression.…”

Section: Introductionmentioning

confidence: 99%

Impact of Attrition, Intercellular Shear in Dry Eye Disease: When Cells are Challenged and Neurons are Triggered

Setten

2020

IJMS

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The mechanical component in the pathophysiology of dry eye disease (DED) deserves attention as an important factor. The lubrication deficit induced impaired mechano-transduction of lid pressure to the ocular surfaces may lead to the dysregulation of homeostasis in the epithelium, with sensations of pain and secondary inflammation. Ocular pain is possibly the first sign of attrition and may occur in the absence of visible epithelial damage. Attrition is a process which involves the constant or repeated challenge of ocular surface tissues by mechanical shear forces; it is enhanced by the thinning of corneal epithelium in severe DED. As a highly dynamic process leading to pain and neurogenic inflammation, the identification of the impact of attrition and its potential pathogenic role could add a new perspective to the current more tear film-oriented models of ocular surface disease. Treatment of DED addressing lubrication deficiencies and inflammation should also consider the decrease of attrition in order to stimulate epithelial recovery and neural regeneration. The importance of hyaluronic acid, its molecular characteristics, the extracellular matrix and autoregulative mechanisms in this process is outlined. The identification of the attrition and recognition of its impact in dry eye pathophysiology could contribute to a better understanding of the disease and optimized treatment regimens.

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Corneal nerves in health and disease

Cited by 207 publications

References 293 publications

The neuroregenerative effects of topical decorin on the injured mouse cornea

The neuroregenerative effects of topical decorin on the injured mouse cornea

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

Impact of Attrition, Intercellular Shear in Dry Eye Disease: When Cells are Challenged and Neurons are Triggered

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