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Nancy A McNamara, Denise Stephens, Jennifer Finley, YuTing Feeling Chen, Sarah Knox; Immune cell infiltration in Aire KO mice leads to corneal nerve degradation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4808. doi: https://doi.org/.
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The nerves of the lacrimal functional unit are crucial in facilitating cross talk between the ocular surface, lacrimal glands, and meibomian glands to maintain ocular surface integrity. When any of these components is compromised, dry eye disease can result. Corneal neuropathy has been observed in both dry eye patients and mouse models of dry eye, yet their role in dry eye disease is poorly understood.
We used the Autoimmune regulator knock out (Aire KO) mouse model of immune mediated, aqueous deficient dry eye to investigate the role of innervation in corneal homeostasis. Corneal nerves in Aire KO mice were examined with immunostaining. Aire KO mice were treated with anti-inflammatory dexamethasone to examine the interaction between corneal inflammation and innervation. Expression of axon guidance markers and neurotrophic factors were measured with qPCR. To identify the mechanism of altered corneal innervation in Aire KO mice we utilized a whole genome expression profile of the Aire KO cornea. Differentially regulated, neurological-related genes were identified with Gene Ontology and candidate regulators of corneal innervation identified with Ingenuity Pathway Analysis.
Decreased corneal innervation is associated with lymphocytic infiltration of the ocular surface in Aire KO mice. QPCR analysis identified misregulated axon guidance and nerve growth associated genes. Inhibition of inflammatory signaling restored the number of corneal nerves in Aire KO mice to wildtype levels, but nerve architecture remained abnormal. To determine the mechanism whereby dexamethasone treatment restored corneal innervation, we identified nerve-related genes that were differentially expressed in Aire KO mice and compared them to known targets of dexamethasone. Potential target genes associated with corneal nerve degradation in dry eye disease included neurotrophic factor receptor Ntrk2, growth factor Vegf, and transcriptional regulators Irf and Stat.
Denervation of the ocular surface in Aire KO mice coincides with immune cell infiltration. This nerve degredation is due, in part, to altered expression of neuromodulators and axon guidance factors and blocking inflammation can restore nerve growth. We have identified potential regulators of corneal innervation and future studies will examine the therapeutic benefits of targeted interventions to slow the progression of dry eye disease.
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