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Diabetic retinopathy (DR), one of the most serious complications of diabetes, has been associated with inflammatory processes. We have recently reported that interleukin (IL)-17A, a proinflammatory cytokine, is increased in the plasma of diabetic patients. Further investigation is required to clarify the role of IL-17A in DR. Ins2Akita (Akita) diabetic mice and high-glucose (HG)-treated primary Müller cells were used to mimic DR-like pathology. Diabetes induced retinal expression of IL-17A and IL-17 receptor A (IL-17RA) in Müller cells in contrast to ganglion cells. Further evidence demonstrated that retinal Müller cells cultured in vitro increased IL-17A and IL-17RA expression as well as IL-17A secretion in the HG condition. In both the HG-treated Müller cells and Akita mouse retina, the Act1/TRAF6/IKK/NF-κB signaling pathway was activated. IL-17A further enhanced inflammatory signaling activation, whereas Act1 knockdown or IKK inhibition blocked the downstream signaling activation by IL-17A. HG- and diabetesinduced Müller cell activation and dysfunction, as determined by increased glial fibrillary acidic protein, vascular endothelial growth factor and glutamate levels and decreased glutamine synthetase and excitatory amino acid transporter-1 expression, were exacerbated by IL-17A; however, they were alleviated by Act1 knockdown or IKK inhibition. In addition, IL-17A intravitreal injection aggravated diabetes-induced retinal vascular leukostasis, vascular leakage and ganglion cell apoptosis, whereas Act1 silencing or anti-IL-17A monoclonal antibody ameliorated the retinal vascular damage and neuronal cell apoptosis. These findings establish that IL-17A xacerbates DR-like pathology by the promotion of Müller cell functional impairment via Act1 signaling.
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참고문헌 (26)
참고문헌 신청
Abcouwer SF / 2013 / Angiogenic factors and cytokines in diabetic retinopathy / J Clin Cell Immunol S1 : 011 ~ 022
Adamis AP / 2008 / Immunological mechanisms in the pathogenesis of diabetic retinopathy / Semin Immunopathol 30 : 65 ~ 84
Aggarwal S / 2002 / IL-17 : prototype member of an emerging cytokine family / J Leukoc Biol 71 : 1 ~ 8
Barber AJ / 2000 / Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group / Invest Ophthal
Bringmann A / 2012 / Muller glial cells in retinal disease / Ophthalmologica 227 : 1 ~ 19
Adamis AP / 2008 / Immunological mechanisms in the pathogenesis of diabetic retinopathy / Semin Immunopathol 30 : 65 ~ 84
Aggarwal S / 2002 / IL-17 : prototype member of an emerging cytokine family / J Leukoc Biol 71 : 1 ~ 8
Barber AJ / 2000 / Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group / Invest Ophthal
Bringmann A / 2012 / Muller glial cells in retinal disease / Ophthalmologica 227 : 1 ~ 19
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