Remodeling of Retinal Architecture in Diabetic Retinopathy: Disruption of Ocular Physiology and Visual Functions by Inflammatory Gene Products and Pyroptosis

Abstract

Diabetic patients suffer from a host of physiological abnormalities beyond just those of glucose metabolism. These abnormalities often lead to systemic inflammation via modulation of several inflammation-related genes, their respective gene products, homocysteine metabolism, and pyroptosis. The very nature of this homeostatic disruption re-sets the overall physiology of diabetics via upregulation of immune responses, enhanced retinal neovascularization, upregulation of epigenetic events, and disturbances in cells' redox regulatory system. This altered pathophysiological milieu can lead to the development of diabetic retinopathy (DR), a debilitating vision-threatening eye condition with microvascular complications. DR is the most prevalent cause of irreversible blindness in the working-age adults throughout the world as it can lead to severe structural and functional remodeling of the retina, decreasing vision and thus diminishing the quality of life. In this manuscript, we attempt to summarize recent developments and new insights to explore the very nature of this intertwined crosstalk between components of the immune system and their metabolic orchestrations to elucidate the pathophysiology of DR. Understanding the multifaceted nature of the cellular and molecular factors that are involved in DR could reveal new targets for effective diagnostics, therapeutics, prognostics, preventive tools, and finally strategies to combat the development and progression of DR in susceptible subjects.

Keywords: chemokines; cytokines; diabetic retinopathy; epigenomics; homocysteine; inflammation; pyroptosis; signaling pathways.

FIGURE 1

Chronic exposure to high glucose and the recognition/sensing of a danger signal from concomitant infection(s) can accelerate inflammation. Abnormal physiological homeostasis is common in the ocular compartment of a patient suffering from diabetes. This augmented nature of inflammation increases expression of mediators that can interact together to activate NF-κB inducing transcription of inflammatory factors such as TNF, iNOS, IL-1β, IL-6, IL-8, IL-17A, adhesion molecule (ICAM-1), eicosanoids (Cox-2) and extracellular matrix degradation enzyme (MMP-9). These events end up compromising the cellular tight junctions and thus communication between ocular cells leading to blood-retinal barrier (BRB) breakdown affecting occludin, ZO-1, connexin 43 and 26. Cox-2, cyclooxygenase-2; HMGB1, high-mobility group box 1; iNOS, inducible nitric oxide synthase; IL-1β, interleukin-1 beta; ICAM-1, intercellular adhesion molecule-1; MMP-9, metalloproteinase-9; TLR4, toll-like receptor 4; TNF, tumor necrosis factor; RBP-4, retinol binding protein-4; ZO-1, zona occludin-1.

FIGURE 2

Growth of abnormal blood vessels in the eyes of diabetics lead to blindness. Hyperglycemic environment increases generation of the advance glycation end products (AGES) harming capillary pericytes and vessels’ permeability thereby spilling fluid contents into the surroundings. The fluid leakage builds up eye pressure that can burst micro-aneurysms. Since the blood vessels fail to deliver enough oxygen and nutrients the eyes upregulate compensatory mechanisms including neovascularization. Additionally, excess glucose also causes formation of hard exudates that can occlude vessels thus further impairing vessels’ ability to nourish the retina thereby leading to vision loss or blindness.

FIGURE 3

Diabetic genome modification. Different environmental determinants modulate genes’ expression and functions as a result of epigenetic modifications. Some are beneficial for health such as microbiome and exercise, but others are harmful like hyperglycemia, pyroptosis, inflammation and oxidative stress disrupting ocular physiology and homeostasis that can lead to diabetic retinopathy. DNMTs, DNA methyltransferases; HMTs, histone methyltransferases; HATs, histone acetyl transferases; circRNA, circular RNA.

FIGURE 4

Perturbation of cellular redox by hyperglycemia promotes oxidative stress-inflammatory axis in diabetic eyes. Imbalance in redox control because of high glucose affects many aspects of ocular physiology including mitochondrial damage and synthesis of higher amounts of advanced glycation end products (AGES) leading to oxidative stress followed by the inflammation. These alterations deplete cells’ abilities to fight off physiological imbalance via antioxidants and glutathione. Oxidative stress also upregulates NADPH oxidase which increases production of various reactive oxygen species (ROS). Apoptosis is also accompanied leading to the loss of retinal cells. Csp3, caspase 3; GSSG, oxidized glutathione (glutathione-s-s-glutathione); GSH, glutathione (a tripeptide-λ-glutamyl-cysteinylglycine); NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; SOD, superoxide dismutase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase.

FIGURE 5

Hyperglycemia inflicts damage leads to neuropathy, diabetic retinopathy (DR), and vision loss via multiple mechanisms. Chronic hyperglycemic environment is a powerful inducer of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) phenotypes in humans. Both PDR and DME can cause mild to severe vision impairment in patients that can result into complete blindness if timely intervention is not sought. PKC, protein Kinase ‘C’; AGES, advance glycation end products; OS, oxidative stress.