Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.
Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.
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应激反应蛋白REDD 1通过维持经典NF-κB信号通路促进糖尿病诱导的视网膜炎症
DOI：
10.1016/j.jbc.2022.102638
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发表时间：
2022-12
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;Toro, Allyson L.;McCurry, Christopher M.;VanCleave, Ashley M.;Stevens, Shaunaci A.;Miller, William P.;Kimball, Scot R.;Dennis, Michael D.
炎症会导致糖尿病引起的视网膜病变的进展。在这里，我们研究了发育中调节的应激反应蛋白和 DNA 损伤反应 1 (REDD1) 在视网膜炎症发展中的作用。在链脲佐菌素 (STZ) 诱导糖尿病 16 周后，在小鼠视网膜中观察到 REDD1 表达增加，并且 REDD1 对于糖尿病诱导的促炎细胞因子表达至关重要。在人视网膜 MIO-M1 Müller 细胞培养物中，REDD1 缺失可防止高血糖条件下促炎细胞因子表达的增加。 REDD1 缺失促进核因子红细胞 2 相关因子 2 (Nrf2) 过度激活；然而，在 REDD1 缺陷细胞中，Nrf2 并不是减少炎症细胞因子表达所必需的。相反，REDD1 通过促进核转录因子 κB (NF-κB) 的激活来增强炎症细胞因子的表达。在暴露于肿瘤坏死因子 α (TNFα) 的 WT 细胞中，炎症细胞因子表达增加，与激活转录因子 4 (ATF4) 依赖性 REDD1 表达和 NF-κB 持续激活相协调。在暴露于 TNFα 的 Müller 细胞培养物和 STZ 糖尿病小鼠的视网膜中，REDD1 缺失促进了 κB 抑制剂 (IκB) 的表达并降低了 NF-κB DNA 结合活性。我们发现 REDD1 通过增强 IκB 激酶复合物的 K63 泛素化和自身磷酸化来作用于 IκB 上游。与 STZ 糖尿病 REDD1+/+ 小鼠相比，STZ 糖尿病 REDD1-/- 小鼠的视网膜中未观察到 IκB 激酶复合物自磷酸化和巨噬细胞浸润。这些发现为糖尿病如何促进视网膜炎症提供了新的见解，并支持 REDD1 维持经典 NF-κB 信号传导激活的模型。
Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor κB (NF-κB). In WT cells exposed to tumor necrosis factor α (TNFα), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-κB. In both Müller cell cultures exposed to TNFα and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of κB (IκB) expression and reduced NF-κB DNA-binding activity. We found that REDD1 acted upstream of IκB by enhancing both K63-ubiquitination and auto-phosphorylation of IκB kinase complex. In contrast with STZ-diabetic REDD1+/+ mice, IκB kinase complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-κB signaling.
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