Investigators see link between inflammation, diabetic retinopathy

Study examining the role of IL-17A in patients with diabetes.

This article was reviewed by Patricia R. Taylor, PhD

The fact that many patients with type I diabetes and most with Type II diabetes will develop diabetic retinopathy (DR) during their lifetimes underscores the importance for investigations to preserve vision.

DR is now the leading cause of blindness in working-age patients with diabetes worldwide, according to Patricia R. Taylor, PhD, who is working to determine how diabetes-mediated low-grade, chronic inflammation induces DR.

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Taylor is an assistant professor in the Department of Ophthalmology and Visual Sciences at Case Western Reserve University in Cleveland, Ohio, and a research health scientist at the Louis Stokes Cleveland VA Medical Center.

In 1 scenario, inflammatory proteins, such as cytokines, are produced continuously and the chemical signaling does not turn off.

This chronicity can become toxic and induce vascular damage leading to DR, she explained during her presentation at the Cleveland Eye Bank Foundation’s virtual Vision Research Symposium in October. Taylor’s research is supported by the Cleveland Eye Bank Foundation.

In patients without diabetes, IL-17A is induced during the course of an infection and turned off at the end of the infection.

However, in many diabetics, production of IL-17A continues unabated. This is also true in other immune disorders in which IL-17A induces tissue and vascular damage. Taylor took her studies a step further to determine if IL-17A is involved in the development of DR.

She described the results of a pilot study of blood collected from individuals without diabetes and patients with type I diabetes who have or do not have DR.

The results indicated that almost no IL-17A was found in the blood of patients without diabetes, but was detected in the blood of all diabetics.

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Additionally, levels of IL-17A were significantly higher (P < 0.01) in patients with diabetes with DR than those without DR.

In another pilot study, Taylor and colleagues investigated vitreous samples from cadaver eyes of individuals without diabetes and diabetics with DR, and they then quantified levels of IL-17A. The investigators found that only the vitreous samples of diabetics with DR had detectable levels of IL-17A.

To achieve a close look at the mechanism of IL-17A in the development of DR, Taylor used a streptozotocin (STZ)-induced diabetes murine model, in which animals were injected into the intraperitoneal with STZ for 5 days.

Seventeen days after the final injection, the development of diabetes was confirmed. During the 17-day period, STZ binds to GLUT-2, which transports STZ into the pancreatic β cell, inhibits glucose metabolism, damages the β cell DNA, and inhibits release of insulin.

This mechanism caused Type I diabetes 22 days after the first injection. Two months after diabetes was confirmed, retinal inflammation, oxidative stress, and cytokine production were present.

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Early-stage DR developed by 8 months, which was characterized by vascular permeability and leakage and capillary degeneration.

At 2 months, IL-17A was detected in the retinas of diabetic mice but not in the nondiabetic controls.1

Eight months following confirmation of diabetes, nondiabetic and diabetic wild-type mice (C57BL/6), were compared with nondiabetic and diabetic IL-17A transgenic-knockout mice to determine if there was a difference in retinal vascular impairment.

To examine vascular leakage, mice were injected with fluorescein isothiocyanate-bovine serum albumin, and the retinas were collected post mortem.

Histopathology showed retinal vascular leakage in the inner and outer nuclear layers and in the outer plexiform layer of the diabetic C57BL/6 mice, but no vascular leakage was present in the IL-17A knockout mice.

Further, capillary degeneration was significantly higher in the diabetic C57BL/6 mice than in the diabetic IL-17A knockout mice.2-3

The investigators concluded that the IL-17A detected in diabetic retinas induces the onset of DR in murine models.

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Similarly, IL-17A was detected only in the vitreous of cadaver eyes of diabetics with DR, whereas IL-17A was detected in the blood of all diabetic donors and was significantly increased in the diabetics with DR.

To further examine the role of IL-17A in the progression of DR, Taylor and colleagues are carrying out a 4-year clinical study at Louis Stokes Cleveland VA Medical Center in collaboration with Case Western Reserve University’s School of Medicine and University Hospitals.

Read more by Lynda Charters


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Patricia R. Taylor, PhD
e:prt11@case.edu
Taylor has no financial interest in this subject matter.

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References

1. Sigurdardottir S, Zapadka TE, Lindstrom SI, et al. Diabetes-mediated IL-17A enhances retinal inflammation, oxidative stress, and vascular permeability. Cell Immunol. 2019;341(7):103921. doi:10.1016/j.cellimm.2019.04.009

2. Lindstrom SI, Sigurdardottir S, Zapadka TE, et al. Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration. J Diabetes Complications. 2019;33(9):668-674. doi:10.1016/j.jdiacomp.2019.05.016

3. Zapadka TE, Lindstrom SI, Taylor BE, et al. RORγT inhibitor-SR1001 halts retinal inflammation, capillary degeneration, and the progression of diabetic retinopathy. Int J Mol Sci. 2020;21(10):3547. doi:10.3390/ijms21103547