Macrophage Migration Inhibitory Factor (MIF) is a Key Player in Dry Eye Disease

Abstract

Purpose: To explore the role of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF), in a murine model of dry eye disease (DED).

Methods: The role of MIF on DED was determined using genetically MIF deficient mice and pharmacological inhibition of MIF. DED was induced with 0.5 mg of scopolamine via subcutaneous injection in wild type (WT) and mice lacking MIF (Mif^-/-), three times a day for 21 days. DED signs, tear volume, ferning pattern and cytology impression were evaluated. Also, eye tissues were collected to determine transcripts of key inflammatory mediators and histopathological damage. In a second set of experiments, we neutralized MIF with ISO-1, an isozaxiline-derivative MIF tautomerase activity-inhibiting small molecule in WT mice, following an acute DED model for 10 days. ISO-1 was given starting on day 3 after DED induction and signs were evaluated, including a recovery phase in both experimental approaches.

Results: When compared to WT, Mif^-/- mice showed attenuated signs of DED like preserved mucin pattern and increased tear volume. Also, Mif^-/- mice maintained conjunctival epithelial cells and less corneal damage, associated with lower levels of TNFα and IL-1β. At recovery phase, Mif^-/- mice presented improved signs. Interestingly, in cornea and conjunctiva the absence of MIF selectively downregulated the transcription of inflammatory enzymes like inos and nox4 whereas displayed enhanced transcripts of il-4, il-13, tgfβ and cox2. Finally, pharmacological inhibition of MIF using ISO-1, replicated the above findings in the mouse model.

Conclusion: MIF is a central positive mediator of the inflammatory process in experimental DED, thus, targeting MIF could be used as a novel therapy in ocular surface inflammatory pathologies.

Keywords: Dry eye disease; ISO-1; MIF; inflammation; ocular surface.