Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea

Abstract

Diabetic peripheral neuropathy (DPN) often leads to neurotrophic ulcerations in the cornea and skin; however, the underlying cellular mechanisms of this complication are poorly understood. Here, we used post-wound corneal sensory degeneration and regeneration as a model and tested the hypothesis that diabetes adversely affects DC populations and infiltration, resulting in disrupted DC-nerve communication and DPN. In streptozotocin-induced type 1 diabetic mice, there was a substantial reduction in sensory nerve density and the number of intraepithelial DCs in unwounded (UW) corneas. In wounded corneas, diabetes markedly delayed sensory nerve regeneration and reduced the number of infiltrating DCs, which were a major source of ciliary neurotrophic factor (CNTF) in the cornea. While CNTF neutralization retarded reinnervation in normal corneas, exogenous CNTF accelerated nerve regeneration in the wounded corneas of diabetic mice and healthy animals, in which DCs had been locally depleted. Moreover, blockade of the CNTF-specific receptor CNTFRα induced sensory nerve degeneration and retarded regeneration in normal corneas. Soluble CNTFRα also partially restored the branching of diabetes-suppressed sensory nerve endings and regeneration in the diabetic corneas. Collectively, our data show that DCs mediate sensory nerve innervation and regeneration through CNTF and that diabetes reduces DC populations in UW and wounded corneas, resulting in decreased CNTF and impaired sensory nerve innervation and regeneration.

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

“…The round-shaped cells observed in the resting corneas expressed CD86, suggesting they are phenotypically mature and/or activated. Our study revealed the presence of DCs along each vertical fiber that crosses the BM and branches into epithelial nerve endings, suggesting a potential role of residential DCs for epithelium innervation by not only releasing neurotrophic factors, such as CNTF39, but also by maintaining direct contact with the nerve as it passes through the BM. This should have implications in our understanding of the immune-nervous interplay in maintaining tissue homeostasis and in corneal response to injury and infection40.…”

“…In the cornea, the transcription of NGF, NT-3, and BDNF was detected in ex vivo human corneas44 while others have shown that NGF was primarily expressed in the limbal epithelial cells45. In the accompanied study39, we showed that the intraepithelial DCs express CNTF, a factor known to promote sensory neuron survival and exon regeneration464748, and that in wounded corneas, all CD11c and HMC-2 positive cells are round-shaped. More interestingly, we showed that DC depletion not only delayed epithelial wound closure26 but also adversely affected sensory nerve regeneration in wounded corneas.…”

Diabetic complications in the cornea

“…In both diabetic patients and animal models, the most severe reduction in nerve fiber and branch density occur in the sub-basal nerve plexus close to the corneal epithelium, possibly explaining the correlation between diabetic keratopathy and corneal neuropathy (De Cillà et al, 2009; He and Bazan, 2012; Wang et al, 2012; Zhivov et al, 2013; Cai et al, 2014; Davidson et al, 2014; Stem et al, 2014). Upon corneal epithelial wounding, severed subbasal nerves regenerate significantly slower in diabetic than in non-diabetic animals (Wang et al, 2012; Gao et al, 2016). The sub-basal nerve alterations in diabetic mice are accompanied by abnormalities of dendritic cells that may serve neurotrophic functions (Leppin et al, 2014; Gao et al, 2016).…”

“…Upon corneal epithelial wounding, severed subbasal nerves regenerate significantly slower in diabetic than in non-diabetic animals (Wang et al, 2012; Gao et al, 2016). The sub-basal nerve alterations in diabetic mice are accompanied by abnormalities of dendritic cells that may serve neurotrophic functions (Leppin et al, 2014; Gao et al, 2016). Several studies have documented corneal neuropathy early in diabetes, before the development of DR (Zhivov et al, 2013; Papanas and Ziegler, 2013; Petropoulos et al, 2015; Szalai et al, 2016).…”

“…Several treatments have also been recently reported to ameliorate some symptoms of diabetes in the cornea using animal models. These include 1,5-isoquinolinediol [poly(ADP-ribose) polymerase inhibitor] that increased corneal sensitivity and epithelial healing in diabetic rats (Byun et al, 2015); ciliary neurotrophic factor (downregulated in the diabetic cornea) that activated corneal epithelial stem cells, increased nerve density, and promoted epithelial healing through the activation of STAT3 in diabetic mice (Zhou et al, 2015); topical nerve growth factor that reduced apoptosis and inflammation in corneas of diabetic rats (Park et al, 2016); interleukin-1 receptor antagonist that increased epithelial wound healing, sensory reinnervation, and reduced apoptosis in diabetic mouse corneas (Yan et al, 2016); substance P that produced similar effects in diabetic mice and high glucose-treated corneal epithelial cells through neurokinin-1 receptor (Yang et al, 2014); curcumin that promoted wound healing and recovery of corneal sensation when used in nanomicelles with intranasal delivery; it may work through reduction of reactive oxygen species (Guo et al, 2016); and topically delivered mitogenic protein lacritin fused with elastin-like polypeptide–based nanoparticles that enhanced corneal epithelial wound healing in NOD diabetic mice (Wang et al, 2014). Although promising, most of these agents need to be studied in more detail including pharmacology and side effects.…”