Exp Mol Med.  2016 Dec;48(12):e280. 10.1038/emm.2016.117.

IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling

• Qiu AW
• Bian Z
• Mao PA
• Liu QH

• KMID: 2367556
• DOI: http://doi.org/10.1038/emm.2016.117

Abstract

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. Ins2(Akita) (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 diabetes-induced 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 exacerbates DR-like pathology by the promotion of Müller cell functional impairment via Act1 signaling.

MeSH Terms

Animals
Apoptosis
Diabetic Retinopathy*
Excitatory Amino Acids
Ganglion Cysts
Glial Fibrillary Acidic Protein
Glutamate-Ammonia Ligase
Glutamic Acid
Humans
In Vitro Techniques
Interleukin-17*
Interleukins
Intravitreal Injections
Leukostasis
Mice
Neurons
Pathology
Plasma
Retina
Retinaldehyde
Vascular Endothelial Growth Factor A
Excitatory Amino Acids
Glial Fibrillary Acidic Protein
Glutamate-Ammonia Ligase
Glutamic Acid
Interleukin-17
Interleukins
Retinaldehyde
Vascular Endothelial Growth Factor A