**Abstract**

As the global burden of diabetes is increasing there is a corresponding increase in the complications associated with the same. Diabetic retinopathy is a sight threatening complication of diabetes mellitus which was considered to be a microvasculopathy. Recent evidence however, has brought to light that inflammation may be a key player in the pathogenesis of this condition. Levels of inflammatory mediators like Hypoxia inducible factor, TNF-α, IL-6 and IL-1B amongst others have been noted to be elevated in the diabetic vitreous gel. The concept of the neurovascular unit better explains the changes that take place resulting in the breakdown of the blood retinal barriers and how these inflammatory mediators affect the morphology of the retina at a cellular level. Glial cells form a key instrument of this neurovascular structure and are also the cells from where the inflammatory response is initiated. Understanding of the pathogenesis of diabetic retinopathy will help us in finding targeted therapies which may provide long term benefits and possible cure. Few anti-inflammatory medications have shown promise albeit in a small clinical or experimental laboratory setting. However, future research may lead to better understanding of the disease and a better pharmacological intervention.

**Keywords:** pathogenesis of diabetic retinopathy, glial cells in diabetic retinopathy, retina inflammation, steroids, cytokines

#### **1. Introduction**

In the past few years, unhealthy lifestyle coupled with obesity has led to a rampant increase in the global burden of diabetes mellitus. As per WHO the global prevalence of the condition was 422 million in the year (2014) with 8.5% of adults aged more than 18 years suffering from this condition. Approximately 1.6 million deaths yearly are supposed to be caused by diabetes alone, this number excludes the mortality associated with cardiovascular events, renal disease and tuberculosis secondary to chronic hyperglycemia [1]. The global burden of diabetes is expected to swell to 642 million adults by the year 2040 with 75% of the affected individuals belonging to low and middle income countries. Diabetic retinopathy affects 1 in 3 adults with diabetes and is one of the major causes of blindness in the working-age population [2].

Diabetic retinopathy (DR) is a major microvascular complication of diabetes and it is categorised into a non-proliferative stage (NPDR) or proliferative stage (PDR) depending on the presence of retinal microvascular changes. The nonproliferative stage is characterised by the presence of microaneurysms, cotton wool spots, vascular tortuosity, retinal haemorrhage and lipid exudation while in the

proliferative stage aberrant new blood vessels develop which are fragile and can extend into the posterior cortical vitreous [3]. Another important element in the vast conundrum of DR is diabetic macular edema (DME). It can occur across all levels of DR changes and compromises central vision. DME is the most common cause of diminished vision in an individual with DR [4].

### **2. The neurovascular unit in diabetic retinopathy**

In recent years a concept of neurovascular unit in diabetic retinopathy has emerged. This is based on the findings that neurodegeneration is one of the earliest changes in a case of diabetic retinopathy. Indeed, a reduction in oscillatory potential in the electroretinogram is the first measurable change in retinal function, being recorded even in cases wherein there is no clinical change suggestive of DR. This indicates that neurodegeneration precedes microvascular abnormalities [5].

The retinal neurovascular unit includes the physical and biochemical interactions amongst the neurons, the vascular beds and the supporting cells of the retinal framework. The neural unit includes the ganglion cells and the glial cells while the vascular component of the unit is made up of the endothelial cells and the pericytes. The neurovascular unit reflects the inter-dependance of the vascular barrier and blood flow regulation on the glial cells, pericytes and neurons as well as their reciprocal dependance on vascular support. Together with the neurovascular unit the retinal pigment epithelium contributes to the formation of the blood retinal barrier [6]. The inner blood retinal barrier (iBRB) encompasses the endothelial cells of the retinal microvasculature which are covered by astrocytes, pericytes and muller cell end-feet. It regulates the transport across the retinal capillaries and maintain the micro-environment of the inner retina. The outer blood retinal barrier (oBRB) comprises the tight junctions of the neighbouring RPE cells and it serves as a filter for nutrients and solutes from the blood [7].

#### **3. Histopathological changes in diabetic retinopathy**

Diabetic retinopathy has been traditionally described as a microvasculopathy, however newer evidence has suggested that inflammation may provide a substantial role in the histopathological changes that are noted in the disease.

#### **3.1 Microvascular changes**

Retinal ischemia is the initiator that propels the plethora of changes that occur in DR. In the initial stages, prior to even the development of visually significant vascular alterations, there is a disruption of vascular auto-regulation which leads to oxygen and nutrient deprivation in the inner retinal layers [8].

Retinal vascular basement membrane thickening is present in the early stages of the disease and is mediated by hyperglycemia. Impaired sugar levels lead to an up-regulation of extracellular matrix proteins, collagen and fibronectin [9]. This thickening of the basement membrane may lead to an impairment in cell to cell communication between the endothelium, pericytes, glial cells and the retinal immune cells, ultimately leading to a loss of function [10]. Loss of pericytes leads to a weakening of the capillary wall; this ultimately results in the development of areas of out-pouching labelled as microaneurysms (MA), which are amongst the first clinically detectable signs of DR [11].

#### *Role of Inflammation in Diabetic Retinopathy DOI: http://dx.doi.org/10.5772/intechopen.100175*

A progressive occlusion of the retinal capillaries is noted on histopathological evaluation of post-mortem specimens. Stitt et al. [10] evaluated trypsin digest preparations of these capillaries and noted them to be acellular tubes of naked basement membrane without endothelial cells. The loss of endothelial cells can be attributed to pericyte death which ultimately culminates into breakdown of the inner blood retinal barrier.

The breakdown of the inner blood retinal barrier would lead accumulation of fluid and exudates in the retinal layers contributing to diabetic macular edema (DME). Fluid exuding out from the superficial capillary plexus leads to accumulation of fluid in the inner nuclear layer while that exuding out from the deep capillary plexus is believed to collect in the outer plexiform layer. Cystoid spaces noted in the macula appear due to liquefaction and necrosis of the muller cells and the production of prostaglandins and inflammatory cytokines [12].

#### **3.2 Neuroglial changes**

The muller cells, astrocytes and microglial cells are present in close vicinity of the retinal blood vessels and help to maintain retina homeostasis. Muller cells play a central role in the retinal metabolism and hence are susceptible to the metabolic alterations of diabetes. An increased production of glial fibrillary acidic protein (GFAP) by the muller cells is noted in the early part of the disease, which plays a key role in gliosis. This is indicative of a state of glial hypertrophy [13].

Microglial cells are the resident inflammatory cells of the retina which get activated in DR. In the early stages of mild DR a hypertrophy of the microglia is noted and the cells are settled along the retinal plexiform layers. When the DR progresses into a proliferative stage the microglial cells are found to be extensively distributed in areas of retinal ischemia and neovascularisation [14]. A strong tendency of the microglial cells to invade the outer retinal layers is also noted in prolonged DR [15].

### **3.3 Neuronal changes**

Overt degeneration of retinal neurons during diabetes is a concept that was first described in the 1960s in post-mortem patient samples. By the late 1990s experimental evidence reinforced this finding by demonstrating that depletion of some neuronal populations occurred in diabetic rodent models, possibly even prior to appearance of obvious microvascular lesions. Apoptosis of the retinal ganglion cells (RGCs) is histologically noted in diabetic retinas. This also accounts for the diminished thickness of the retinal nerve fibre layer on optical coherence tomography (OCT). It is believed that hyperglycemia induces a down-regulation of neuronal growth factors thereby contributing to programmed cell death [16].
