Autophagy in dry eye disease: Therapeutic implications of autophagy modulators on the ocular surface

Abstract

Dry eye disease (DED) is a chronic ocular surface disorder, associated with inflammation, which can cause severe morbidity, visual compromise, and loss of quality of life, affecting up to 5-50% of the world population. In DED, ocular surface damage and tear film instability due to abnormal tear secretion lead to ocular surface pain, discomfort, and epithelial barrier disruption. Studies have shown the involvement of autophagy regulation in dry eye disease as a pathogenic mechanism along with the inflammatory response. Autophagy is a self-degradation pathway in mammalian cells that reduces the excessive inflammation driven by the secretion of inflammatory factors in tears. Specific autophagy modulators are already available for the management of DED currently. However, growing studies on autophagy regulation in DED might further encourage the development of autophagy modulating drugs that reduce the pathological response at the ocular surface. In this review, we summarize the role of autophagy in the pathogenesis of dry eye disease and explore its therapeutic application.

Keywords: Autophagy modulators; corneal autophagy; inflammation; ocular surface dry eye disease.

Figure 1

Causes of dry eye. DED caused by external environmental stressors such as ultraviolet rays, allergy medications, smoking, chemicals, heat, and even contact lenses

Figure 2

Types of autophagy. Autophagy broadly classified into three categories. (a) Macroautophagy, (b) chaperon-mediated autophagy, (c) microautophagy. All the forms ultimately deliver the substrates as cargo so they can be recycled by lysosomes

Figure 3

Molecular marker-associated autophagy regulation under dry eye condition: Schematic representation of autophagic lysosomal degradation pathway and its related proteins involved in different types of stressors

Figure 4

Effects of autophagy modulators in dry eye. (a) Figure shows inflammatory response and autophagy regulation on human corneal epithelial cells treated with or without autophagy modulators. (b) Mice models of dry condition show differential regulation of autophagy treated with autophagy modulators such as rapamycin, LYN-1604, WAY-100635. (c) Topical administration of trehalose in dry eye patients shows reduced levels of inflammatory cytokines and clinical symptoms respectively

Figure 5

Signaling pathway interactions of anti-inflammatory molecules with trehalose. Schematic diagram shows molecular signaling networks (autophagy, inflammation) associated with cyclosporine, lifitegrast, and trehalose