Interleukin-17A attenuates photoreceptor cell apoptosis in streptozotocin-induced diabetic mouse model

Diabetic retinopathy (DR) represents an important microvascular complication of diabetes, which is the top etiology of vision impairment worldwide. Although interleukin (IL)-17A is increasingly implicated in DR development, the underlying cellular mechanisms remain poorly defined. This work aims to evaluate IL-17A levels in the retina of streptozotocin (STZ)-induced diabetic mice and elucidate their potential roles. We found IL-17A was upregulated in diabetic retina after intraperitoneal injection of STZ and high-glucose (HG)-cultured primary Müller cells. IL-17A knockout (IL-17A−/−) downregulated glial fibrillary acidic protein (GFAP) and inhibited the conversion of proneurotrophin-3 (proNT-3) to mature NT-3 in retinal specimens from diabetic mice as well as in Müller cells cultured under HG conditions. Induced apoptosis and upregulated Bax and cleaved caspase-3 were observed in retinal specimens from IL-17A−/− diabetic mice and photoreceptor (661 W) cells after co-culture with IL-17A−/− Müller cells. Moreover, RNA interference-induced gene silencing of tyrosine kinase C receptor (TrkC) in 661 W cells reversed the anti-apoptotic effect of IL-17A under HG conditions. Taken together, our findings suggest that IL-17A/NT-3/TrkC axis regulation suppresses apoptosis in photoreceptor cells, providing a new treatment strategy for DR.糖尿病视网膜病变（Diabetic retinopathy, DR）是糖尿病的重要微血管并发症，也是全球范围内视力损伤的首要病因。尽管白细胞介素（interleukin, IL）-17A在DR发病机制中的作用愈发受到重视，但其潜在的细胞调控机制仍未明确。本研究旨在检测链脲佐菌素（streptozotocin, STZ）诱导的糖尿病小鼠视网膜组织中IL-17A的表达水平，并阐明其潜在生物学功能。我们发现，在腹腔注射STZ诱导的糖尿病小鼠视网膜，以及高糖（high-glucose, HG）培养的原代穆勒胶质细胞中，IL-17A的表达均显著上调。IL-17A基因敲除（IL-17A−/−）可下调糖尿病小鼠视网膜标本及高糖培养的穆勒胶质细胞中的胶质纤维酸性蛋白（glial fibrillary acidic protein, GFAP）表达，并抑制前体神经营养因子-3（proneurotrophin-3, proNT-3）向成熟NT-3的转化。在IL-17A−/−糖尿病小鼠的视网膜标本，以及与IL-17A−/−穆勒胶质细胞共培养的感光细胞（661 W）中，均可观察到细胞凋亡被诱导，同时Bax蛋白及裂解型半胱氨酸天冬氨酸蛋白酶-3（cleaved caspase-3）的表达水平显著上调。此外，在661 W细胞中通过RNA干扰沉默酪氨酸激酶C受体（tyrosine kinase C receptor, TrkC）的表达，可逆转IL-17A在高糖条件下的抗凋亡作用。综上，本研究结果表明，IL-17A/NT-3/TrkC信号轴可抑制感光细胞凋亡，为糖尿病视网膜病变的治疗提供了全新的潜在策略。