REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice.
REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice.
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DOI：
10.1016/j.jbc.2023.104991
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发表时间：
2023-08
影响因子：
4.8
通讯作者：
Dennis, Michael D.
中科院分区：
文献类型：
--
作者：
Sunilkumar, Siddharth;Vancleave, Ashley M.;Mccurry, Christopher M.;Toro, Allyson L.;Stevens, Shaunaci A.;Kimball, Scot R.;Dennis, Michael D.
越来越多的证据支持炎症在糖尿病引起的视网膜并发症的早期发展和进展中的作用。我们最近发现，在发育和DNA损伤反应1 （REDD1）中调节的应激反应蛋白通过维持核转录因子NF-κB的典型激活来促进糖尿病诱导的视网膜炎症。本研究旨在确定糖尿病小鼠视网膜中REDD1促进NF-κB活化的信号事件。我们观察到16周链脲佐菌素（STZ）诱导的糖尿病小鼠视网膜中REDD1的表达增加，并发现REDD1是糖尿病抑制糖原合成酶激酶3β (GSK3β)在S9的抑制性磷酸化所必需的。在人视网膜io - m1 m<s:1> ller细胞培养中，在高血糖条件下，REDD1缺失阻止了GSK3β的去磷酸化，并增加了NF-κB的激活。表达一种组成型活性GSK3β变异体可在缺乏REDD1的细胞中恢复NF-κB的激活。在高血糖条件下的细胞中，GSK3β敲低可通过阻止κB激酶复合物自磷酸化抑制剂和κB降解抑制剂抑制NF-κB活化和促炎细胞因子的表达。在stz -糖尿病小鼠的视网膜和暴露于高血糖条件下的<s:1> ller细胞中，GSK3抑制降低了NF-κB活性，阻止了促炎细胞因子表达的增加。与接受对照的stz -糖尿病小鼠相比，GSK3抑制剂治疗的stz -糖尿病小鼠视网膜未观察到巨噬细胞浸润。总的来说，这些发现支持了一个模型，其中糖尿病增强了redd1依赖性的GSK3β激活，以促进典型的NF-κB信号传导和视网膜炎症的发展。
Increasing evidence supports a role for inflammation in the early development and progression of retinal complications caused by diabetes. We recently demonstrated that the stress response protein regulated in development and DNA damage response 1 (REDD1) promotes diabetes-induced retinal inflammation by sustaining canonical activation of nuclear transcription factor, NF-κB. The studies here were designed to identify signaling events whereby REDD1 promotes NF-κB activation in the retina of diabetic mice. We observed increased REDD1 expression in the retina of mice after 16 weeks of streptozotocin (STZ)-induced diabetes and found that REDD1 was essential for diabetes to suppress inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at S9. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented dephosphorylation of GSK3β and increased NF-κB activation in response to hyperglycemic conditions. Expression of a constitutively active GSK3β variant restored NF-κB activation in cells deficient for REDD1. In cells exposed to hyperglycemic conditions, GSK3β knockdown inhibited NF-κB activation and proinflammatory cytokine expression by preventing inhibitor of κB kinase complex autophosphorylation and inhibitor of κB degradation. In both the retina of STZ-diabetic mice and in Müller cells exposed to hyperglycemic conditions, GSK3 inhibition reduced NF-κB activity and prevented an increase in proinflammatory cytokine expression. In contrast with STZ-diabetic mice receiving a vehicle control, macrophage infiltration was not observed in the retina of STZ-diabetic mice treated with GSK3 inhibitor. Collectively, the findings support a model wherein diabetes enhances REDD1-dependent activation of GSK3β to promote canonical NF-κB signaling and the development of retinal inflammation.
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