Dendritic cell dysfunction and diabetic sensory neuropathy in the cornea
Nan Gao, … , Haijing Sun, Fu-Shin Yu
Nan Gao, … , Haijing Sun, Fu-Shin Yu
Published April 11, 2016
Citation Information: J Clin Invest. 2016;126(5):1998-2011. https://doi.org/10.1172/JCI85097.
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Research Article Inflammation

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.

Authors

Nan Gao, Chenxi Yan, Patrick Lee, Haijing Sun, Fu-Shin Yu

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Figure 5

CNTF expression and colocalization with CD11c-positive cells in NL and DM corneas with or without epithelial debridement.

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CNTF expression and colocalization with CD11c-positive cells in NL and D...
Both NL and DM corneas were wounded as described in Figure 1. (A) UW and healing corneas (22 hpw) were collected and processed for RT-PCR screening of neurotrophins. Results were first normalized with β-actin levels and then compared with NL levels (value 1), presented as the fold change (n = 5). **P < 0.01 and *P < 0.05, by 2-way ANOVA with Bonferroni’s post test. (B) WMCM showing colocalization of CD11c and CNTF in UW normal and DM corneas. Note that, although faint, CNTF red staining was also visible where CD11c-positive cells were located. Scale bar: 75 μm. (C) WMCM showing CD11c and CNTF colocalization in healing corneas of NL and DM mice. Enlarged bottom panel images (“I”) show CD11c-negative and CNTF-positive cells. L, limbal region. Scale bars: 150 μm; original magnification, ×3.8 (enlarged “I” images). (D) Both CD11c- and CNTF-positive cells in the corneas were quantitated using the particle-counting function in ImageJ. Results are presented as the average number of CD11c- or CNTF-positive cells (particles) in the selected area (n = 3). **P < 0.01, by 2-tailed, unpaired Student’s t test. Two independent experiments were performed.