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Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood‐retinal barrier in diabetic retinopathy
Author(s) -
Jo Dong Hyun,
Yun JangHyuk,
Cho Chang Sik,
Kim Jin Hyoung,
Kim Jeong Hun,
Cho ChungHyun
Publication year - 2019
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23542
Subject(s) - microglia , retinal , blood–retinal barrier , biology , retina , microbiology and biotechnology , occludin , neuroglia , retinal pigment epithelium , diabetic retinopathy , tumor necrosis factor alpha , streptozotocin , muller glia , immunology , tight junction , inflammation , endocrinology , stem cell , diabetes mellitus , neuroscience , central nervous system , progenitor cell , biochemistry
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.