Abstract
The corneal epithelium consists of stratified epithelial cells, sparsely interspersed with dendritic cells (DCs) and a dense layer of sensory axons. We sought to assess the structural and functional correlation of DCs and sensory nerves. Two morphologically different DCs, dendriform and round-shaped, were detected in the corneal epithelium. The dendriform DCs were located at the sub-basal space where the nerve plexus resides, with DC dendrites crossing several nerve endings. The round-shaped DCs were closely associated with nerve fiber branching points, penetrating the basement membrane and reaching into the stroma. Phenotypically, the round-shaped DCs were CD86 positive. Trigeminal denervation resulted in epithelial defects with or without total tarsorrhaphy, decreased tear secretion, and the loss of dendriform DCs at the ocular surface. Local DC depletion resulted in a significant decrease in corneal sensitivity, an increase in epithelial defects, and a reduced density of nerve endings at the center of the cornea. Post-wound nerve regeneration was also delayed in the DC-depleted corneas. Taken together, our data show that DCs and sensory nerves are located in close proximity. DCs may play a role in epithelium innervation by accompanying the sensory nerve fibers in crossing the basement membrane and branching into nerve endings.
Highlights
The cornea is the most heavily innerved tissue in the body primarily supplied by small-diameter C-fiber sensory neurons, with densely distributed sensory nerve endings in the sub-basal space of the epithelium, termed the sub-basal nerve plexus[1]
We report that Dendritic cells (DCs) and sensory nerves co-localize within the sub-basal nerve plexus of the cornea and that their interactions are critical in corneal homeostasis after wounding
We showed the presence of two types of DCs with different morphologies and phenotypes in adult corneas: those with dendrites (CD86 negative) that interconnected with several nerve endings in the subbasal plexus, and round-shaped DCs (CD86 positive) that were co-localized with nerve fiber branching points in the subbasal plexus and that perpendicularly penetrate the basement membrane (BM)
Summary
The cornea is the most heavily innerved tissue in the body primarily supplied by small-diameter C-fiber sensory neurons, with densely distributed sensory nerve endings in the sub-basal space of the epithelium, termed the sub-basal nerve plexus[1]. Some of the DCs at the central cornea insert processes between epithelial cells, similar to that of the vertically-oriented sensory nerve endings These processes serve to sample antigens from the environment[19,20]. Both sensory nerves and DCs function as sentinels at the mucosal surface of the cornea; while sensory nerves utilize nociceptors to sense chemical and temperature changes, DCs use pattern recognizing receptors such as Toll-like receptors to detect “foreigners”. They are located in close proximity to one another, within the spaces between the basement membrane and the epithelial sheet in the cornea. Using streptozotocin-induced type I diabetic mouse model, we recently demonstrated that DCs mediate sensory nerve innervation and regeneration through CNTF; diabetes reduces the population of DCs in unwounded and wounded corneas, resulting in a decrease in CNTF concentration and impaired sensory nerve innervation and regeneration
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