Dry Eye Disease: Emerging Approaches to Disease Analysis and Therapy

Abstract

Dry eye disease (DED) is among the most common ocular disorders affecting tens of millions of individuals worldwide; however, the condition remains incompletely understood and treated. Valuable insights have emerged from multidisciplinary approaches, including immunometabolic analyses, microbiome analyses, and bioengineering. Furthermore, we have seen new developments in clinical assessment approaches and treatment strategies in the recent past. Here, we review the emerging frontiers in the pathobiology and clinical management of DED.

Keywords: DED treatment; clinical signs; dry eye disease; eye-on-a-chip; immunometabolism; microbiota; omics.

Figure 1

Oxidative metabolism and changes in normal microbiota contribute to dry eye disease (DED) by inducing inflammation at the ocular surface. Reactive oxygen species (ROS) directly or indirectly activates the NLRP3 inflammasome by increasing tear-film instability and osmolarity. DED-associated changes in the microbiota is in turn associated with changes in the metabolic profile of the ocular surface which changes the balance between pro- and anti-inflammatory arms of the immune system toward the proinflammatory pathways. The induced inflammation is presumably the cornerstone of DED pathology. Abbreviations: DED: dry eye disease, FoxO3: Forkhead box O3, LPS: lipopolysaccharide, MnSOD: manganese superoxide dismutase, NLRP3: NLR family pyrin-domain-containing 3, ROS: reactive oxygen species, Sirt1: sirtuin 1, SOD: superoxide dismutase, Treg: regulatory T-cell.

Figure 2

Metabolic requirements of Th17 and Treg responses. Th17 cells are dependent on aerobic glycolytic metabolism. Inducers of lipid oxidative metabolism inhibit Th17 cell generation. Conversely, Treg generation is enhanced by treatments that promote lipid oxidative metabolism and suppressed by inhibitors of lipid transport such as etomoxir. Cholesterol derivatives are required for Th17 cell differentiation and blockade of cholesterol biosynthesis, for example, with ketoconazole, suppresses the generation of Th17 cells but has no effect on Tregs. Figure taken from Binger, K.J. et al. with permission [33].

Figure 3

Microbiome and Th17 autoimmunity. Research in intestinal mucosal microbiome has revealed a link with Th17 response and epithelial integrity. These studies may provide useful hints to researchers working on other mucosal linings. Furthermore, direct links between the intestinal microbiota and ocular diseases have been suggested, including a link with uveitis [50], and dry eye disease [49]. Figure taken from Kenya Honda et al. [51] with permission.

Figure 4

An engineered model of evaporative dry eye disease. (a) Evaporation causes the break-up of the tear film and increases tear osmolarity that together leads to a loss of homeostasis. (b) Absorption of tears into the Schirmer strips in the healthy and dry eye models. Tear absorption is visualized by the smearing of the blue ink within the strips. (c) Tear osmolarity in the DED (closed triangle) and the normal (closed circle) models. Human clinical data of osmolarity are from normal subjects (open circle) and DED subjects (open triangle). (d) Keratographs showing concentric rings projected on the human ocular surface (top) and the engineered ocular surface (bottom). (e) Representative images of projected ring patterns on the engineered ocular surface of the healthy (top row) and the DED (bottom row) groups captured at t = 0 s (left column) and t = 10 s (right column). (f) Spatial mapping of tear film break-up time in the normal (top) and the DED (bottom) models. Different colors in the representative circular heat maps indicate different tear break-up times. (g) Fluorescein staining of the eye model and human subjects. (h) Concentrations of inflammatory mediators (IL-8, TNF-α, IL-1β, and MMP-9) in the normal (circle) and the DED (triangle) groups plotted against the duration of culture. Figure taken from Jeongyun Seo et al. with permission [109].