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 1

Quantitation of sensory nerves in UW and healing NL and DM mouse corneas.

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Quantitation of sensory nerves in UW and healing NL and DM mouse corneas...
A 2-mm epithelial debridement wound was created and allowed to heal for 18 hours in NL corneas and for 24 hours in DM corneas, resulting in similarly sized remaining wounds. UW and healing corneas were stained with β-tubulin III Ab for sensory nerve labeling. The WMCM images were acquired with ROI scanning of a defined area and assembled automatically to show whole corneas from B6 mice (A). To quantify the innervation in UW corneas, the major nerve fibers, defined as those that extended to at least one-third of the corneal diameter, starting from the limbus, with or without branches, were marked (arrows); the length was measured; and the branches were manually counted for each marked fiber and presented as the total length (B) and number of branches (C) per cornea. Central areas with a swirling pattern of nerve endings (framed area “I” in A, top panel) are shown at higher magnification (A, middle panel), and innervation was calculated with ImageJ as the percentage of area positive for β-tubulin III staining (D). Innervation in healing corneas was also calculated as the percentage of areas positive for β-tubulin III staining (E). Results are representative of 2 independent experiments (n = 3 each). **P < 0.01 and *P < 0.05, by 2-tailed, unpaired Student’s t test. Scale bars: 125 μm (A, top and bottom panels) and 25 μm (A, middle panel). W, wounded.