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Takefumi Yamaguchi, Deshea L Harris, Kazunari Higa, Jun Shimazaki, Ulrich von Andrian, Pedram Hamrah; Neurogenic Immune Homeostasis: Peripheral Innervation Maintains Avascularity and Immune Privilege of the Cornea. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4034.
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© ARVO (1962-2015); The Authors (2016-present)
The cornea, an immune privileged tissue, is the most densely innervated tissue in the body. Recently, we have demonstrated that corneal nerves participate in trafficking and motility of immune cells, in particular dendritic cells (DCs). The aim of the current study is to investigate if neuronal dysfunction leads to the loss of immune privilege in the cornea.
After trigeminal axotomy, corneal cytokines (interleukin [IL]-1β, -2, -4, -6, -10, -17a, interferon-ɤ, tumor necrosis factor [TNF]-α) were measured using multiplex bead assay. Cornea were stained for CD45 and MHC-2 after trigeminal axotomy. Corneal hem- and lymph-angiogenesis were assessed by immunohistochemistry staining with CD31 and LYVE-1. Orthotopic corneal transplantation was carried out by grafting C57BL/6 donor corneas to BALB/c recipients. To see the effect of corneal nerve damage on graft survival, trigeminal axotomy was performed in the recipient BALB/c one week prior to corneal transplantation. Ear swelling was measured to assess the donor specific delayed-type hypersensitivity (DTH).
After trigeminal axotomy, pro-inflammatory cytokines in the cornea were significantly increased; IL-1β (1.8 folds) and IL-6 (113 folds) from 4 days, and IL-17a (2.3 folds) and TNFα (2.7 folds) from 7days. From day 1 after trigeminal axotomy, the density of corneal CD45+ cells (490±94 cells/mm2 in the center; 2.6 folds, 782±122 in the periphery; 3.1 folds) significantly increased. From day 14, MHC-2+ cell (168±53 in the center; 3.9 folds, 364±62 in the periphery; 2.2 folds) significantly increased. Corneal neovessel area was significantly increased from 6% to 38% at 7 days after trigeminal axotomy. In addition, corneal lymphatic vessel area was significantly increased from 7% to 40% after trigeminal axotomy. Axotomy prior to corneal transplantation resulted in rejection of all grafts (100 % n = 11, vs sham-treated 67% n =12, P < 0.001). Moreover, donor-specific DTH response in mice was positive at 2 weeks after allogeneic corneal transplantation with trigeminal axotomy, although it was negative in mice at 2 weeks after allogeneic corneal transplantation without trigeminal axotomy.
Neurogenic immune homeostasis is a critical process, whereby the peripheral nervous system directly maintains corneal immune privilege.
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