Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea

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.

The Effects of Aging on Corneal and Ocular Surface Homeostasis in Mice

“…7,14 A number of human and mouse studies have established a structural relationship between dendritic cells and corneal nerves, with current hypotheses suggesting that elevated DC density leads to changes in the corneal nerves, and subsequently, a disruption to corneal homeostasis. 27,41 Similar to our findings in mice, human studies have identified no significant change to corneal epithelial DCs with aging in a healthy population. 42 In the context of inflammation, numerous studies have highlighted a negative correlation between corneal nerves and DC density, suggesting a functional relationship between corneal nerve pathology and DC activation in the corneal epithelium.…”

“…A smaller population of DCs also exist in the corneal stroma. 26,27 For clarity, reference to DCs in this present study will relate only to corneal epithelial DCs.…”

“…21 Recent mouse studies have demonstrated that DCs and corneal nerves form physical contacts within the SBNP, suggesting a direct interaction between the immune system and peripheral nerves. 27 Furthermore, pharmacological depletion of the resident DC population has been shown to be correlated with a decline in corneal nerve structure under homeostatic conditions. 27 This is in contrast to the reported negative correlation between DC density and nerve density in a range of corneal pathologies caused by infectious keratitis.…”

“…27 Furthermore, pharmacological depletion of the resident DC population has been shown to be correlated with a decline in corneal nerve structure under homeostatic conditions. 27 This is in contrast to the reported negative correlation between DC density and nerve density in a range of corneal pathologies caused by infectious keratitis. 30,31 However, whether there is a change in the neuroimmune interaction or in the density and morphology of DCs in the aging mouse cornea is still unclear.…”

Kinetics of corneal leukocytes by intravital multiphoton microscopy

“…Induction of 5 light burns to the cornea likely results in multiple sources of chemokine and cytokine release and in turn, the multidirectional chemotactic migration seen in our results. Another likely confounding factor in the change in cell motility is the loss of corneal nerve fibers in these locations, with close proximity between CLs and corneal nerves having been reported in the steady-state cornea (27,79). Other inflammatory states, such as single epithelial injury or suture placement, resulting in a single source of chemokine release, will likely show directional chemotactic migration.…”