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Arsia Jamali, Maria J Lopez, Victor Sendra, Deshea L Harris, Pedram Hamrah, ; Plasmacytoid Dendritic Cells Demonstrate Vital Neuro-protective Properties in the Cornea and Induce Corneal Nerve Regeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4355.
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© ARVO (1962-2015); The Authors (2016-present)
Plasmacytoid dendritic cells (pDCs), a recently identified resident bone marrow-derived cell population in the cornea, are potent orchestrators of innate and adaptive immunity. Despite the traditional perspective that immune cells are deleterious for nerve regeneration, more recent evidence suggests that immune cells may have beneficial effects in neuronal regeneration. This study aims to characterize the role of pDCs in corneal nerve maintenance, function, and regeneration
Corneal pDCs were locally depleted by constitutive subconjunctival injection of 30ng Diphtheria toxin (DT) in BDCA2-DTR mice. Wild-type C57BL/6 mice treated with DT and BDCA2-DTR mice receiving PBS served as controls. Corneal sensation was evaluated by an 8.0 thread; corneas were stained for βIII-tubulin (pan-neuronal marker) and underwent confocal microscopy. Corneal nerve density was measured on stacked confocal micrographs via NeuronJ. Relative corneal NGF mRNA levels were assessed via real-time PCR. Naïve and sutured corneas underwent flow cytometry for CD45 (pan-leukocyte marker), Siglec-H, PDCA-1, B220 (pDC markers), and NGF. Chi square, T-test and ANOVA were used to assess statistical significance.
Upon local depletion of resident corneal pDCs, central cornea nerve density was reduced to 120.3±14.9 mm/mm2 on day1, 21.9±14.8 on day 3, and 1.1±0.7 on day 7 compared to 143±8.1 in control corneas (p<0.001). In the peripheral cornea, pDC depletion resulted in nerve diminishment to 102.1±16.9, 20.9±8.6, 5.3±3.9, on day 1, 3, and 7, respectively compared to 112±9.3 in controls (p<0.001). Corneal sensation was diminished in all pDC-depleted mice by day 3 (p<0.01). Relative NGF mRNA levels were decreased to 22.5% and 17.9% of controls after pDC depletion on day 7 and 14, respectively (p<0.01). Flow cytometry showed that NGF co-stains with pDCs in both naïve and suture-induced inflamed corneal single cell suspensions. After 7-day pDC depletion, mice were kept for 14 days to allow pDC repopulation. Upon pDC repopulation, corneal nerves regenerated to 81.5± 0.2 in periphery and to 48.4±5.0 in central cornea, and corneal sensation was recovered (p<0.001).
Resident corneal pDCs harbor neurotrophic properties through secretion of NGF and are crucial for corneal nerve maintenance and function. Moreover, corneal pDCs induce corneal nerve regeneration after corneal nerve loss.
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