Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood‐retinal barrier in diabetic retinopathy

Abstract

Inner and outer blood‐retinal barriers (BRBs), mainly composed of retinal endothelial cells and retinal pigment epithelial (RPE) cells, respectively, maintain the integrity of the retinal tissues. In this study, we aimed to investigate the mechanisms of the outer BRB disruption regarding the interaction between RPE and microglia. In mice with high‐fat diet‐induced obesity and streptozotocin‐induced hyperglycemia, microglia accumulated on the RPE layer, as in those after intravitreal injection of interleukin (IL)‐6, which is elevated in ocular fluids of patients with diabetic retinopathy. Although IL‐6 did not directly affect the levels of zonula occludens (ZO)‐1 and occludin in RPE cells, IL‐6 increased VEGFA mRNA in RPE cells to recruit microglial cells. In microglial cells, IL‐6 upregulated the mRNA levels of MCP1, MIP1A, and MIP1B, to amplify the recruitment of microglial cells. In this manner, IL‐6 modulated RPE and microglial cells to attract microglial cells on RPE cells. Furthermore, IL‐6‐treated microglial cells produced and secreted tumor necrosis factor (TNF)‐α, which activated NF‐κB and decreased the levels of ZO‐1 in RPE cells. As STAT3 inhibition reversed the effects of IL‐6‐treated microglial cells on the RPE monolayer in vitro, it reduced the recruitment of microglial cells and the production of TNF‐α in RPE tissues in streptozotocin‐treated mice. Taken together, IL‐6‐treated RPE and microglial cells amplified the recruitment of microglial cells and IL‐6‐treated microglial cells produced TNF‐α to disrupt the outer BRB in diabetic retinopathy.

Microglia and Inflammatory Responses in Diabetic Retinopathy

“…In a hyperglycemic environment, several mediators of inflammation contribute to the breakdown of the BRB. In STZ-diabetic mice, the retinal pigment epithelium (RPE) secretes VEGF which in turn triggers the recruitment of microglia to the RPE ( 102 ). Concurrently, microglia-derived TNF-α decreases protein levels of zonula occludens (ZO-1) in RPE cells, thereby disrupting the outer BRB in DR ( 102 ).…”

“…In STZ-diabetic mice, the retinal pigment epithelium (RPE) secretes VEGF which in turn triggers the recruitment of microglia to the RPE ( 102 ). Concurrently, microglia-derived TNF-α decreases protein levels of zonula occludens (ZO-1) in RPE cells, thereby disrupting the outer BRB in DR ( 102 ). Likewise, BRB breakdown was prevented in TNF-α knockout rats after six months of STZ induced diabetes implying that TNFα plays an important role in BRB disruption ( 103 ).…”

A Network Pharmacology Based Analysis of The Potential Mechanisms of Compound Danshen Dripping Pill for Treatment of Diabetic Retinopathy

“…But over time, it disrupts the outer blood-retinal barriers (BRB) and acts as a pathologic angiogenic stimulus. 77,78 These studies indicate the feasibility of CDDP against DR by targeting these predicted targets and their biological processes. Our results showed that CDDP might regulate multiple targets of DR, including in ammatory cytokines and growth factors et al…”

“…The results showed that the common targets were mainly concentrated in the advanced glycation end-products and receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, uid shear stress and atherosclerosis, apoptosis, tumor necrosis factor (TNF), hypoxia-inducible factor-1 (HIF-1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and VEGF signaling pathway, which regulate many biological processes like oxidative stress, blood pressure, hemodynamic change, apoptosis, in ammation, retinal ischemia, proliferation and differentiation. [19][20][21][22][23][24][25][26]…”

The RPE Cell and the Immune System

“…These initial studies have been expanded to investigate the cross-talk between RPE and microglia. Jo and associated demonstrated that interaction between these cells determines the integrity of the outer blood-retinal barrier in murine diabetic retinopathy [44]. This interaction was mediated by the presence of IL-6 and the production of TNF-α by the microglia cells.…”