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Aubrey Hargrave, Madhavi Chintalapati, Carolina Lema, Clifton Wayne Smith, Alan Robert Burns; The upregulation of cytokines, chemokines, and growth factors during diet-induced corneal degeneration and recovery in a mouse model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2066.
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In a murine model of pre-diabetic metabolic syndrome, mice fed a high fat diet (HFD) exhibit a decline in corneal sensitivity, nerve density, and epithelial thickness. These changes are reversed when the mice resume a normal chow diet (ND). The purpose of this study is to determine if the morphological and functional pathology is associated with changes in the cytokine profile of the cornea.
Six week old male C57BL/6 mice (n=113) were fed a HFD (42% Kcal milk fat) for 5, 10, and 15 weeks. Controls were age-matched mice on a ND. Diet reversal (DR) mice were fed a HFD for 5 weeks, followed by a ND for 5 or 10 weeks. Tissue homogenates from corneas were collected at 5, 10, and 15 weeks. At 10 weeks, corneas were also collected and incubated in cell culture medium for 6h to evaluate secreted products. All samples were tested for 32 analytes using a multiplex Luminex assay (Millipore, MCYTMAG-70K-PX32). Statistics were performed using one-way ANOVA with Dunnett’s post-test, with a p-value ≤ 0.05 considered significant.
Of the 32 proteins tested, 26 were detected in cornea homogenates and 25 were detected in cell culture medium. There was a 1.3-16.6 fold increase in the level of the proteins following consumption of a HFD. At 10 weeks, the following were significantly upregulated in HFD and DR corneas: Interleukin (IL)-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), leukemia inhibitory factor (LIF), chemokine (C-X-C motif) ligand 1, CXCL2, CXCL9, chemokine (C-C motif) ligand 2 and vascular endothelial growth factor (VEGF). With the exception of GM-CSF, CXCL9 and CCL3, the same mediators were also significantly elevated in cell culture medium from excised corneas. Additional mediators elevated in HFD mice but not in DR mice included IL-1α, IL-10, IL-12p40 and CCL3.
A HFD increases levels of cytokines, chemokines, and growth factors in the cornea, many of which have recognized roles in neurogenic inflammation and nerve degeneration. The sustained upregulation of some mediators after 15 weeks on a HFD may explain the continued decline in nerve function seen at this time. Lastly, some inflammatory mediators that increase on a HFD return to baseline in DR mice, and this reduction may contribute in part to the recovery of nerve function, density and epithelial thickness.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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