IL‐10‐induced modulation of macrophage polarization suppresses outer‐blood‐retinal barrier disruption in the streptozotocin‐induced early diabetic retinopathy mouse model

Abstract Diabetic retinopathy (DR) is associated with ocular inflammation leading to retinal barrier breakdown, vascular leakage, macular edema, and vision loss. DR is not only a microvascular disease but also involves retinal neurodegeneration, demonstrating that pathological changes associated with neuroinflammation precede microvascular injury in early DR. Macrophage activation plays a central role in neuroinflammation. During DR, the inflammatory response depends on the polarization of retinal macrophages, triggering pro‐inflammatory (M1) or anti‐inflammatory (M2) activity. This study aimed to determine the role of macrophages in vascular leakage through the tight junction complexes of retinal pigment epithelium, which is the outer blood‐retinal barrier (BRB). Furthermore, we aimed to assess whether interleukin‐10 (IL‐10), a representative M2‐inducer, can decrease inflammatory macrophages and alleviate outer‐BRB disruption. We found that modulation of macrophage polarization affects the structural and functional integrity of ARPE‐19 cells in a co‐culture system under high‐glucose conditions. Furthermore, we demonstrated that intravitreal IL‐10 injection induces an increase in the ratio of anti‐inflammatory macrophages and effectively suppresses outer‐BRB disruption and vascular leakage in a mouse model of early‐stage streptozotocin‐induced diabetes. Our results suggest that modulation of macrophage polarization by IL‐10 administration during early‐stage DR has a promising protective effect against outer‐BRB disruption and vascular leakage. This finding provides valuable insights for early intervention in DR.