张力反应增强子结合蛋白通过上调脂联素 2 促进糖尿病性神经炎症和认知障碍。

Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2.

机构信息

Department of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea.

Department of Biochemistry, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, 52727, Republic of Korea.

出版信息

J Neuroinflammation. 2021 Nov 29;18(1):278. doi: 10.1186/s12974-021-02331-8.

BACKGROUND

Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood.

METHODS

We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell' medium/HG-treated mouse hippocampal HT22 cells.

RESULTS

Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood-brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / -) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells.

CONCLUSIONS

These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.

背景

糖尿病患者的循环炎症介质增加，这些介质被认为是神经炎症和记忆缺陷的潜在原因。张力反应增强结合蛋白（TonEBP）促进糖尿病神经炎症。然而，TonEBP 在糖尿病大脑中的确切作用尚未完全了解。

方法

我们在糖尿病小鼠模型中使用高脂肪饮食（HFD）喂养的小鼠或 HFD/链脲佐菌素（STZ）处理的小鼠。在 2 型糖尿病患者中测量循环 TonEBP 和脂钙蛋白-2（LCN2）水平。使用 TonEBP 单倍不足小鼠来研究 TonEBP 在 HFD/STZ 诱导的糖尿病小鼠中的作用。此外，RAW 264.7 巨噬细胞给予脂多糖（LPS）/高葡萄糖（HG）处理。使用 siRNA，我们研究了 TonEBP 敲低对 RAW264 细胞培养基/HG 处理的小鼠海马 HT22 细胞的影响。

结果

实验性糖尿病小鼠或伴有认知障碍的 2 型糖尿病患者的循环 TonEBP 和 LCN2 水平升高。TonEBP 单倍不足改善了糖尿病表型，包括脂肪组织巨噬细胞浸润、神经炎症、血脑屏障渗漏和记忆缺陷。TonEBP 单倍不足减少了糖尿病小鼠的系统和海马 LCN2 蛋白。与糖尿病野生型小鼠相比，TonEBP（+/-）小鼠的海马血红素加氧酶-1（HO-1）表达减少。特别是，我们发现 TonEBP 在糖尿病海马中与 LCN2 启动子结合，这种结合被 TonEBP 单倍不足所废除。此外，TonEBP 敲低可减弱脂多糖/高葡萄糖处理的小鼠海马 HT22 细胞中的 LCN2 表达。