*4.4.4.3 Stromal cell-derived factor-1*

Stromal cell-derived factor-1 (SDF-1) is a chemokine that is up-regulated in response to tissue damage and is involved in stimulation and mobilisation of cells involved in tissue repair and cellular migration, differentiation, and proliferation of endothelial progenitor cells [124]. SDF-1 repairs after ischemic injury by binding to its receptor, CXCR4 and recruits the progenitors of endothelial cells from the bone marrow. The levels off SDF-1 in vitreous have been found to be on higher side in DME and PDR patients [125]. Studies have demonstrated that inhibiting the N-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1 axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction and this signalling axis could include the therapeutic potential for other diseases involving pathological neovascularization and or macular edema [126].

#### *4.4.4.4 Fractalkine*

Fractalkine (CX3CL1) is an intriguing chemokine that plays a central role in the nervous system. Expression of CX3CL1 on neurons and its receptor CX3CR1 on microglia facilitates a privileged interaction, playing important roles in regulating the function and maturation of these cells. CX3CL1 is reported to have neuroprotective and anti-inflammatory activities [127]. Studies suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signalling disrupts the vascular integrity in retina during systemic inflammation [128].

#### *4.4.4.5 Macrophage migration inhibitory factor*

Macrophage migration inhibitory factor (MIF) is a chemokine that stimulates macrophages causing their recruitment at sites of inflammation, increasing their adherence, motility, and phagocytosis. It also prevents random migration of macrophages [129]. Studies indicate increased levels of MIF in the vitreous of patients with PDR and a significant association between MIF levels and grades of fibrous proliferation, suggesting the possibility that MIF may play a part in the development of the proliferative phase of PDR [130].

#### *4.4.5 Intercellular adhesion molecule-1 (ICAM1)*

ICAM-1 is a cell surface glycoprotein, which serves as an adhesion receptor that is known for regulating leukocyte recruitment from circulation to sites of inflammation. In addition to vascular endothelial cells, ICAM-1 expression is also induced on epithelial and immune cells in response to inflammatory stimulation. ICAM-1 also serves as a biosensor to transduce outside-in-signalling via association of its cytoplasmic domain with the actin cytoskeleton following ligand engagement of the extracellular domain. Thus, ICAM-1 has emerged as a master regulator of many essential cellular functions both at the onset and at the resolution of pathologic conditions [131]. Increased expression of adhesion molecule leads to activation of RAGE, oxidative stress, vascular leakage in the diabetic retina, capillary non perfusion, and damage of endothelial cells and the adhesion of leukocytes to the endothelium and expression of retinal vascular adhesion molecules such as VEGF [132]. ICAM-1 is the primary adhesion molecule involved in DR and its levels in vitreous are elevated in patients with active PDR [114].

## **5. Therapy aimed at inflammatory targets**

Maintenance of a good glycemic control is considered to be the most important modifiable factor influencing the stage and progression of diabetic retinopathy. However, inhibition of retinal inflammation may also reduce the degree of

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

retinopathy despite the presence of a hyperglycaemic state. High-dose aspirin, COX-2 inhibitors and corticosteroids have been used, either experimentally in animal models or therapeutically in humans, and found to have a beneficial effect in reducing DR changes. However, these drugs are associated with unfavourable side effects especially when used over a long-term course. Hence other alternatives should be looked at. These alternatives can include RAGE inhibitors, minocycline, derivatives of salicylates and inhibitors of TNF-α and 5-lipoxygenase. Salicylates inhibit the nuclear migration and possibly activation of NF-κB in retinal neurons [133]. Evidence is accumulating showing that lipid supplementation with omega 3 polyunsaturated fatty acids (especially DHA) has a beneficial effect in DR [134].

Retinal inflammatory changes in diabetics have been found to be inhibited by therapies wherein the primary target is at a different site. The antihypertensive telmisartan, angiotensin receptor blocker (Type I receptor) was found to suppress retinal leukostasis and expression of VEGF and ICAM-1 [135]. Similarly, in diabetic animal models, Candesartan reduces the presence of acellular retinal capillaries, iNOS and nitric oxide [136]. The beneficial effect of statins on DR has also been reported by Kang et al. in 2019 [137]. The authors evaluated patients with diabetes and dyslipidemia and found that statin use was associated with a decreased prevalence of DR and a lower need for invasive therapy for vision threatening diabetic retinopathy complications. This therapeutic benefit can be attributed to the pleiotropic property of statins, which also function as anti-inflammatory agents. Tuuminen et al. [138] found a decreased intravitreal levels of pro-angiogenic factors, transforming growth factor B1 and matrix metalloproteinase 9 in individuals treated with simvastatin.

The role of salicylates in DR has been studied extensively, following the initial reports by Powell and Field in 1964 [20]. Administration of aspirin in animal models has found to reduce retinal capillary degeneration but conflicting results were reported in human trials. The Early Treatment Diabetic Retinopathy Study (ETDRS) is particularly of note in this case. The ETDRS report number 8 results indicated that aspirin has no clinically beneficial effect on the progression of retinopathy in individuals taking 650 mg of aspirin per day [139]. However, we have to take into account that the anti-inflammatory dose of aspirin is much higher than what was being administered in the study. Salicylates have shown to reduce insulin resistance in the retina in a Type II diabetic rat model as per Jiang Y and co-workers [140].

TNF-α is a key molecule in the inflammatory puzzle thus it serves as an attractive pharmacological target. Subcutaneous injection of TNF-α trap (Eternacept) was found to significantly reduce retinal inflammation, retinal cell injury and vascular permeability in diabetic rats [141]. However, no clinical trials have reported this effect till date. A small pilot study of 4 patients who were administered Infliximab (TNF-α antibody) showed a decrease in central macular thickness and a corresponding improvement in visual acuity [142].

Inhibition of leukostasis is another mechanism that can be targeted in antiinflammatory therapy for DR. Leukocyte function associated antigen-1 (LFA-1) is an integrin molecule and is extremely important for leukocyte-endothelial cell interactions. SAR-1118 is a topical antagonist of LFA-1 and has shown a dose dependant reduction of leukostasis and vascular leakage in a diabetic rat model [143]. Anti CD49a neutralising antibody blocks the interaction between very late antigen-4 (VLA-4) and VCAM-1 and has also shows efficacy in reducing leukostasis [144].

Apart from their antibiotic activity both Minocycline and Doxycycline are known to possess neuro-protective and immunomodulatory properties, such as inhibiting production of NO, prostaglandins, TNF-α and caspases [145]. A small study of minocycline in 5 patients with DME showed improvement in visual acuity with reduction in macular edema [146]. Another study involving doxycycline demonstrated an improvement in perimetric parameters in individuals with severe NPDR or PDR [147].

Photobiomodulation is another prospective therapy which has shown promise in a small clinical study of patient with non-centre involving diabetic macular edema [148]. It consists of series of brief illumination with specific wavelengths of light emitted from a laser. It has shown to affect the signalling pathways within the cells and inhibits diabetes induced leukostasis, ICAM-1 expression and production of reactive oxygen species [149].
