Galectins in the Pathogenesis of Common Retinal Disease

Abstract

Diseases of the retina are major causes of visual impairment and blindness in developed countries and, due to an ageing population, their prevalence is continually rising. The lack of effective therapies and the limitations of those currently in use highlight the importance of continued research into the pathogenesis of these diseases. Vascular endothelial growth factor (VEGF) plays a major role in driving vascular dysfunction in retinal disease and has therefore become a key therapeutic target. Recent evidence also points to a potentially similarly important role of galectins, a family of β-galactoside-binding proteins. Indeed, they have been implicated in regulating fundamental processes, including vascular hyperpermeability, angiogenesis, neuroinflammation, and oxidative stress, all of which also play a prominent role in retinopathies. Here, we review direct evidence for pathological roles of galectins in retinal disease. In addition, we extrapolate potential roles of galectins in the retina from evidence in cancer, immune and neuro-biology. We conclude that there is value in increasing understanding of galectin function in retinal biology, in particular in the context of the retinal vasculature and microglia. With greater insight, recent clinical developments of galectin-targeting drugs could potentially also be of benefit to the clinical management of many blinding diseases.

Keywords: VEGF; age-related macula degeneration; angiogenesis; diabetic retinopathy; leakage; retina.

FIGURE 1

Classification of galectin proteins. Functionally, galectins always have at least two CRDs, either located within the same polypeptide or by multimerisation. Three galectin subtypes can be distinguished based on the structural organization of the conserved carbohydrate recognition domain (CRD). Prototypic galectins contain a single CRD forming homodimers. Tandem repeat galectins contain two distinct CRDs. Chimeric galectins contain a single CRD and can form multimers (only Gal-3 belongs to this group).

FIGURE 2

Structure and morphology of the retina. Schematic illustration of the neural circuit of the retina showing the five neuronal cell types: photoreceptors, horizontal, bipolar, amacrine and ganglion and supporting cells. Photoreceptor outer segments (cones and rods) are apically associated and supported by the RPE. The blood supply to the outer retina is from the choroid situated between Brunch’s membrane and the sclera.

FIGURE 3

Structure and morphology of the retinal vasculature (A) Full colour retinal fundus image of a normal human eye. The optic disc resides in the middle of the retina where major blood vessels branch throughout the eye except one area–the fovea, which is situated in the centre of the macula (B) Structural organisation of the retinal vasculature. Schematic illustration of the three (superficial, intermediate and deep) main layers of the retinal vasculature. The photoreceptor layer is completely avascular (C) Schematic representation, at the microvascular (capillaries) level, of the neurovascular unit, which is formed by endothelial cells (EC), pericytes (PC), astrocytes endfeet (AE), Müller cells (MC), which also interact with all retinal neuronal cells (NC) as illustrated in Figure 2.

FIGURE 4

Normal and diseased human retina (A) Optical coherence tomography (OCT) image sectioning the macular area of a healthy retina (right). The corresponding fundus image of the macular area (green box) is shown on the left, in which the section of tomographic scan indicated by the arrow. The fovea depression is seen in the centre. RNFL = retinal nerve fibre layer. RGC = retinal ganglionic cells. INL = inner nuclear layer. ONL = outer nuclear layer. ELM = external limiting membrane. IS/OS = inner segment/outer segments. (B) OCT image of a macula of a patient with DMO. Severe oedema results in fluid filled cysts around the fovea, subretinal fluid just underneath the fovea, and posterior hyaloid detachment. Retinal layering and fovea depression are lost (C) Wide field angiography image of a PDR eye. Clearly visible are observed abnormal growth of blood vessels on the optic nerve, neovascularization (new blood vessels), microaneurysm and capillary non-perfusion.

FIGURE 5

Gal-1 and Gal-3 involvement in main features of retinal vascular diseases. See Section Mechanisms of Galectin Function in Retinal Dysfunction for further details.

FIGURE 6

Unresolved areas in retinal galectins research. (A) Proposed roles of Gal-1 and Gal-3 in the regulation of angiogenesis and vascular leakage. Stimulated by hyperglycaemia, inflammation, and hypoxia, Müller cells (MC) secrete Gal-1, Gal-3 and VEGF-A, which activate VEGF receptors on endothelial cells (EC). Autocrine stimulation of EC may also occur. The molecular nature of the galectin-responsive VEGF receptors is still unclear. (B) Proposed interplay of galectin expression and receptor glycosylation in the activation of VEGF2 in response to pathogenic stimuli in the retina. (C) Proposed mechanism of the CNS/retinal galectins roles during neuroinflammatory response. Gal-1 and Gal-3 drive the microglia response toward both neurodegeneration and -protection. (D) Schematic of the intracellular and extracellular functions of galectins in any retinal cell type. They can be protective or disruptive.