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Takefumi Yamaguchi, Kazunari Higa, Murat Dogru, Yoshiyuki Satake, Jun Shimazaki; Neurogenic Homeostasis of Corneal Immunity; Peripheral Nerve Regulates Innate Immunity through Vasoactive Intestinal Peptide. Invest. Ophthalmol. Vis. Sci. 2016;57(12):335.
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© ARVO (1962-2015); The Authors (2016-present)
Numerous studies have demonstrated the essential roles of the peripheral nervous system as the neuroendocrine system, mediating the secretion of neuropeptides and/or neurotransmitters to suppress the excessive inflammatory reactions in autoimmune diseases, such as inflammatory bowel disease. We recently reported that loss of corneal nerve leads to corneal inflammation and the loss of neurogenic immune privilege. The purpose of this study was to evaluate the effect of vasoactive intestinal peptide (VIP) on innate immunity in denervated cornea.
Trigeminal axotomy (TA) or sham procedure were performed in 6-8 week-old male BALB/c mice. Corneal opacity grading, immunohistochemistry (IHC) and corneal cytokine levels were determined 24 hours after 20μg of LPS instillation onto the cornea with or without TA and topical VIP treatment (more than N=3). Corneal opacity grading was as follows; grade 0: clear, grade 1: mild opacity, grade 2: moderate opacity, grade 3: severely dense opacity. IHC was performed with anti-CD45 and anti-CD11b to evaluate immune cells density. Corneas (N=6) were homogenized and cytokine levels of interleukin (IL)-2, -4, -6, -8,-17a, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured using multiplex beads assay.
Corneal opacity grading was 0±0 in normal cornea, 0.4±0.5 after only LPS instillation, 1.2±0.4 after only TA, 3.0±0.0 after both LPS+TA, and 0.6±0.4 after LPS+TA with VIP treatment (P < 0.01). LPS instillation after TA resulted in increased CD45+ cell density (normal; 210±15 cells/mm2, only LPS; 878±75, LPS+TA; 3472±320; p < 0.001) and CD11b+ cell density (normal; 10±10, only LPS; 154±21, LPS+TA; 1542±132; p < 0.001). IL-6, TNF-α and IFN-γ levels were significantly higher after LPS+TA (7.1±2.0 pg/ml, 44.0±7.3, 6730±231) than after only LPS (2.1±0.6, 6.7±2.7, 314±94) or after only TA (3.7±0.3, 6.4±1.9, 2729±402) . Topical VIP treatment decreased IL-6 TNF-α and IFN-γ levels after LPS+TA (2.2±0.5, 6.1±4.2, 716±207, all P<0.05).
Our results identify that increased immune reaction by LPS instillation in denervated cornea, whereby the peripheral nervous system regulates innate immunity in the cornea. In the absence of corneal nerves, severe immune reaction can be decreased by exogenous VIP treatment.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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