Interleukin-4 Correlated to Inflammation Regulation in Diabetic Retinopathy

Interleukin-4 (IL-4), a cytokine intraocular inflammatory mediator, has been strongly implicated in inflammation regulation, tissue repair, T helper 2 cell-mediated immunity, and vascular remodeling. It may also aid in the prevention of diabetic retinopathy (DR).¹

The recent INSPIRE study, presented at the 43^rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, has examined the baseline IL-4 levels in patients with diabetes and various levels of diabetic retinopathy. The study aimed to determine the possible relationship between IL-4 and retinal vasculature and macular thickness.¹

Recent research has indicated much greater vitreous levels of IL-4, among a variety of other cytokines, in patients with proliferative DR. IL-4 was positively correlated with vitreous concentrations of VEGF; this, coupled with its substantially greater prevalence, potentially indicates a significant role of activation of vascular proliferation and local inflammation in proliferative DR pathogenesis.²

The prospective, randomized study, presented by Megan Steinkerchner, MD, Vanderbilt Eye Institute, evaluated patients at a single academic tertiary center. Aqueous cytokine samples, peripheral blood markers, and retinal imaging were collected every 4 months over the course of 3 years. These samples were tested for VEGF and 23 other cytokine varieties.¹

A total of 328 eyes of 164 patients were included in the study, with a median age of 63 years (range 27-79 years). Half of the patients (n = 82) were male, and 74% (n = 122) were white. Among the included eyes, 14% (n = 46) had no DR, 72% (n = 236) had nonproliferative DR, and 14% (n = 46) had proliferative DR.¹

Baseline aqueous IL-4 levels were substantially different between the 3 groups. The median IL-4 levels were .41 pg/ml (range 0-.58 pg/ml) for patients with no retinopathy, .5 pg/ml (range 0-.78 pg/ml) for patients with mild to moderate nonproliferative DR, .74 pg/ml (range 0-1.15 pg/ml) in moderate to severe nonproliferative DR, and .86 pg/ml (range .54-1.28 pg/ml) in proliferative DR.¹

Investigators noted odds ratios (ORs) of IL-4 levels with no DR as reference was 1.97 (95% CI, 1.01-3.86; P = .05) in mild to moderate nonproliferative DR, 4.2 (95% CI, 1.94-9.09; P <.001) in moderate to severe nonproliferative DR, and 7.78 (95% CI, 3.18-19.04; P <.001) in proliferative DR.¹

Steinkerchner and colleagues also noted a positive correlation between IL-4 and HbA1c at cohort entry (r = .19, P <.001), and increased levels were associated with worse DR severity when adjusted for age, sex, and HbA1c in an ordinal regression model (OR 2.17; P <.001). Aqueous IL-4 levels were not correlated with optical coherence tomography biomarkers, namely central subfield thickness, macular volume, and parafoveal/perifoveal thickness.¹

Notably, baseline increased IL-4 levels were significantly correlated with a smaller foveal avascular zone (FAZ) area and perimeter. In the proliferative DR cohort, they were also correlated with average vessel caliber on OCT angiography in the deep retinal layer (P <.05). IL-4 was also associated with reduced FAZ perimeter and increased vessel density in the superficial layer in the proliferative DR group (P <.05).¹

Ultimately, investigators determined that IL-4’s role in the pathogenesis of DR could potentially aid in the prevention of DR in future patients.¹

“This finding brings forth the question of additional inflammatory mediators in the pathogenesis of diabetic retinopathy,” wrote Steinkerchner and colleagues.¹

References

1. Steinkerchner M, Lee L, Sheng J, Veach L, et al. Aqueous Interleukin-4 Levels in Relation to Macular Thickness and Retinal Vasculature in Diabetic Retinopathy: INSPIRE Trial. Poster presented at the 43^rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, July 30-August 2, 2025.

2. Chernykh VV, Varvarinsky EV, Smirnov EV, Chernykh DV, Trunov AN. Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy. Indian J Ophthalmol. 2015;63(1):33-36. doi:10.4103/0301-4738.151464