Contribution of Corneal Neovascularization to Dendritic Cell Migration into the Central Area during Human Corneal Infection

Abstract

Compared with the peripheral corneal limbus, the human central cornea lacks blood vessels, which is responsible for its immunologically privileged status and high transparency. Dendritic cells (DCs) are present in the central avascular area of inflamed corneas, but the mechanisms of their migration to this location are poorly understood. Here, we investigated the contribution of vessel formation to DC migration into the central cornea, and analyzed the DC chemotactic factors produced by human corneal epithelial (HCE) cells. Using human eyes obtained from surgical procedures, we then assessed vessel formation, DC distribution, and activin A expression immunohistochemically. The results demonstrated increased numbers of vessels and DCs in the central area of inflamed corneas, and a positive correlation between the number of vessels and DCs. Activin A was expressed in the subepithelial space and the endothelium of newly formed blood vessels in the inflamed cornea. In infected corneas, DCs were present in the central area but no vascularization was observed, suggesting the presence of chemotactic factors that induced DC migration from the limbal vessels. To test this hypothesis, we assessed the migration of monocyte-derived DCs toward HCE cell supernatants with or without lipopolysaccharide (LPS) stimulation of HCE cells and inflammatory cytokines (released by HCE cells). DCs migrated toward tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and activin A, as well as LPS-stimulated HCE cell supernatants. The supernatant contained elevated TNF-α, IL-6, and activin A levels, suggesting that they were produced by HCE cells after LPS stimulation. Therefore, vessels in the central cornea might constitute a DC migration route, and activin A expressed in the endothelium of newly formed vessels might contribute to corneal vascularization. Activin A also functions as a chemotactic factor, similar to HCE-produced TNF-α and IL-6. These findings enhance our understanding of the pathophysiology of corneal inflammation during infection.

Identification and characterization of dendritic cell subtypes in preserved and cultured cadaveric human corneolimbal tissue on amniotic membrane

“…In comparison, it has already been reported that inflammation and corneal vessel formation contributed to higher numbers of activated DCs that expressed CD1a, langerin, DC‐SIGN and CD83 in the central corneal area (Narumi et al. ). In addition, in vivo confocal microscopy showed increased numbers of distributed DCs in the central part of the cornea with immune‐mediated inflammation (Mastropasqua et al.…”

“…However, the distribution and the activation state of DCs in the cornea might also be changed due to patients’ backgrounds (Narumi et al. ). The more central distribution of activated DCs in our study might therefore also be a result of previous cataract surgeries (80% pseudophakic donor corneas) or higher donor age (mean age 86).…”

“…Furthermore, previous experiments have shown that inflammation induces migration of resident DC populations from the limbal area into the central part of the cornea (Hamrah et al 2003c;Hamrah & Dana 2007). However, the distribution and the activation state of DCs in the cornea might also be changed due to patients' backgrounds (Narumi et al 2014). The more central distribution of activated DCs in our study might therefore also be a result of previous cataract surgeries (80% pseudophakic donor corneas) or higher donor age (mean age 86).…”

Rare giant corneal keloid presenting 26 years after trauma: A case report

“…The growth of neovascularization into the cornea is a complex process, in which multiple mediators such as inflammatory regulators, cytokines, growth factors, and matrix metalloproteinases interact. The neovascularization itself can assist dendritic cell (DC) migration into the central area[ 12 ]. DCs promote keloid proliferation by secreting a series of cytokines that activate inflammatory pathways in the cornea[ 13 ].…”

Lymphatic vessels identified in failed corneal transplants with neovascularisation

“…Several studies to date have investigated the role of lymphatics in various corneal pathologies. One recent paper by Narumi et al on human corneas examined the role of dendritic cells and their relationship to corneal lymphatic and blood vessels in cases with corneal infection 6. Additional studies investigated lymphatics in human corneal samples with varying underlying pathologies including abnormal vessel growth 7–9.…”