Diabetic retinopathy (DR) is a complication of diabetes mellitus that affects the vessels of the retina. DR develops in 30% of patients with diabetes and is the leading cause of blindness in the population aged 20–74 years. With long-term diabetes of more than 15 years, DR can develop in 98% of patients with type 1 diabetes (T1D) and more than 80% of patients with type 2 diabetes (T2D).

At a late stage, diabetic retinopathy leads to a rapid deterioration in vision, pathological vascular proliferation, vitreous hemorrhage, and retinal detachment. These changes are irreversible. Patients are advised to have regular eye examinations to detect DR early to prevent them.

Late-stage DR is treated with drugs against vascular endothelial growth factor (anti-VEGF), laser photocoagulation, intravitreal glucocorticoid injections, and surgery. However, these treatments cannot eliminate DR and have serious side effects. Therefore, the most effective way to prevent the progression of DR is regular monitoring at an early stage of the disease.

Inflammation in Diabetic Retinopathy

The early stage of DR begins with inflammation. Inflammation occurs before the development of microvascular lesions. Therefore, markers of inflammation can be used for the early diagnosis of DR. One of the inflammatory markers is interferon-gamma (IFN-gamma). Activation of inflammatory cytokines such as IFN-gamma, IL-1β, IL-6, and IL-10 is the primary indicator of persistent mild inflammation, which can increase vascular permeability and accelerate the progression of DR. In DR, IFN-gamma levels are elevated in tears, vitreous fluid, and serum.

Interferons in Diabetic Retinopathy

Interferons are signaling molecules that have antiviral, antiproliferative, and immunomodulatory properties. Almost all mammalian cells produce interferons after being stimulated by foreign molecules.

IFN-alpha regulates innate and adaptive immune responses. Therefore, IFN-alpha affects DR and the pathological processes of other eye and systemic diseases, such as conjunctival papilloma, uveitis, HIV infection, diseases of the central nervous system, and malignant tumors.

Interferons gamma and alpha are involved in inflammation in DR. When used to treat ocular diseases or other dysfunctions, IFN-alpha can cause concomitant visual changes such as inflammation of the eyeball and pathological retinal vascular proliferation.

Interferon-Gamma Role in Diabetic Retinopathy

IFN-gamma is the only type II interferon. IFN-gamma is closely associated with innate and adaptive immunity. Interferon-gamma can inhibit cell proliferation, stimulate the activity of cytotoxic T cells, and the biosynthesis of cytokines. In addition, IFN-gamma and IFN-alpha can protect pancreatic β-cells in T1D from death.

Interferon-gamma plays a central role in the development of DR. IFN-gamma has inflammatory properties. Inflammation is the leading cause of impaired capillary patency, hypoxia, and subsequent increased vascular endothelial growth factor (VEGF). IFN-gamma triggers and maintains chronic inflammation in the diabetic retina, leading to vascular dysfunction and destruction of the blood-retinal barrier. Under the influence of IFN-gamma, the cornea and vitreous body also change pathologically.

In addition, IFN-gamma correlates with blood glucose levels, systolic blood pressure, and platelets. Therefore, IFN-gamma can be used to predict microvascular complications in diabetes.

However, IFN-gamma plays a protective role in the kidneys in type II diabetes. IFN-gamma may counteract renal fibrosis by inhibiting fibroblast activation and proliferation and reducing collagen synthesis.

The role of IFN-gamma in the pathological formation of new blood vessels is controversial. On the one hand, IFN-gamma can prevent and slow down the development of vascular proliferation by increasing the proportion of pro-inflammatory M1 macrophages. On the other hand, IFN-gamma accelerates blood vessel formation by increasing VEGF expression and activating inflammatory cells and cytokines.

Interferon-Alpha Role in Diabetic Retinopathy

IFN-alpha is a type I interferon that triggers an immune response against infections and neoplasms. In T1D, due to its autoimmune properties, IFN-alpha is involved in the early death of pancreatic β-cells that produce insulin, which lowers blood glucose levels. In T1D, plasma levels of IFN-alpha increase, and blockade of the type I interferon receptor and anti-IFN-alpha antibodies may reduce the incidence of T1D.

Interferon-alpha-2 has a therapeutic effect in a wide range of ocular dysfunctions. IFN-alpha-2a can suppress intraocular inflammation. After subcutaneous administration of 6 million/IU IFN-alpha-2a 3 times a week for 10 months, patients with advanced DR improved visual acuity and stopped the pathological proliferation of blood vessels after total laser photocoagulation.

However, treatment of hepatitis C with interferon-alpha increases the risk of retinopathy. However, these patients rarely experience decreased visual acuity and subjective symptoms. In addition, glucose tolerance increased during treatment with recombinant IFN-alpha, both in patients with hepatitis C without diabetes and in patients with diabetes.

Interferon-alpha-2a can be used to treat diabetic retinopathy. IFN-alpha prevents visual impairment, suppresses pathological proliferation of blood vessels, and stimulates the barrier function of retinal endothelial cells.

The clinical effect of IFN-alpha-2a was observed only in patients after total laser photocoagulation and patients with active vascular proliferation but not meeting the criteria for laser photocoagulation treatment. However, treatment with IFN-alpha can cause side effects such as flu-like symptoms and elevated liver enzymes.

IFN-alpha in diabetes mellitus and diabetic retinopathy have conflicting functions. On the one hand, overexpression of IFN-alpha can lead to the development of T1D. On the other hand, IFN-alpha can treat diabetic retinopathy and diabetic macular edema and improve pancreatic β-cell survival.

Interferon-alpha is used in eye diseases such as uveitis, vernal keratoconjunctivitis, and diabetic macular edema. In ocular surface tumors, intralesional injection of IFN-alpha-2a before surgery significantly reduced tumor size and pathological vascular proliferation. The tumor’s edges were better defined, which facilitated the subsequent removal of the tumor. The treatment prognosis improved, and the risk of recurrence and metastasis decreased.

Conclusion

In the early stages of DR, patients do not experience clinical symptoms. However, the changes that appear at a later stage are irreversible. The earlier DR is detected, the better the prognosis. Therefore, regular ophthalmological examinations are necessary for the early diagnosis of DR.

Interferon-gamma can be used as a marker for diabetic retinopathy. Diabetic retinopathy begins with inflammation. IFN-gamma promotes inflammation and microvascular lesions associated with diabetes mellitus. The level of IFN-gamma correlates with the level of glucose in the blood, which can predict the microvascular complications of diabetes mellitus. IFN-gamma correlates with glycated hemoglobin and inflammatory cytokines such as IL-1β and IL-3. Nevertheless, IFN-gamma is less sensitive to dietary changes and better reflects eye inflammation than glucose and glycated hemoglobin. The level of IFN-gamma can be used to assess the risk of developing retinopathy in diabetes, the rate of progression to the late stage of DR, and the prognosis of the disease.

At an early stage of DR, patients are advised to control risk factors: blood pressure, blood sugar, lipid levels, and smoking. For the treatment of advanced DR, anti-VEGF is prescribed. However, this treatment brings short-term results and is accompanied by side effects. Blocking VEGF cannot completely stop the progression of DR or repair retinal damage but simply delays the rate of disease progression and alleviates symptoms. Anti-VEGF is only a temporary measure.

Interferon-alpha-2 is effective in various eye diseases: uveitis, cystic macular edema, and superficial tumors. The clinical efficacy of IFN-alpha was observed only in the late stage of DR after total laser photocoagulation of proliferating vessels and in diabetic macular edema and ongoing vasodilation. In addition, IFN-alpha increases glucose tolerance and may improve prognosis.

Interferon-alpha may help patients with diabetic retinopathy. During treatment with IFN-alpha, it is essential to continue ophthalmic examinations to monitor the progression of the disease.

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Role of interferons in diabetic retinopathy

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