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.
Highlights
Unlike most other organs, the central part of the human cornea lacks blood vessels and lymphatic vessels
Mayer [5] described the characteristics of dendritic cells (DCs) in corneal buttons that were enucleated for transplantation purposes, and demonstrated the presence of Langerhans cells (LCs) and immature DCs in the human corneal epithelium, and DC-SIGN-positive (i.e., CD209+) DCs in the stroma
DC-SIGN+ DCs were observed in the subepithelial space and in the stroma
Summary
The central part of the human cornea lacks blood vessels and lymphatic vessels. Mayer [5] described the characteristics of DCs in corneal buttons that were enucleated for transplantation purposes, and demonstrated the presence of LCs and immature DCs (imDCs) in the human corneal epithelium, and DC-SIGN-positive (i.e., CD209+) DCs in the stroma. These studies reported that the number of APCs in the central part of the cornea was lower than that in the paracentral and peripheral regions
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