Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea.
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea.
Biochem Biophys Res Commun. 2018 Sep 5;503(2):798-802. doi: 10.1016/j.bbrc.2018.06.078. Epub 2018 Jun 18.
Acute lung injury (ALI) is an acute failure of the respiratory system with unacceptably high mortality, for which effective treatment is urgently necessary. Infiltrations by immune cells, such as leukocytes and macrophages, are responsible for the inflammatory response in ALI, which is characterized by excessive production of pro-inflammatory mediators in lung tissues exposed to various pathogen-associated molecules such as lipopolysaccharide (LPS) from microbial organisms. α-Ketoglutarate (α-KG) is a key metabolic intermediate and acts as a pro-inflammatory metabolite, which is responsible for LPS-induced proinflammatory cytokine production through NF-κB signaling pathway. Mitochondrial NADP-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme catalyzing the conversion of isocitrate to α-KG with concurrent production of NAPDH. Therefore, we evaluated the role of IDH2 in LPS-induced ALI using IDH2-deficient mice. We observed that LPS-induced inflammation and lung injury is attenuated in IDH2-deficient mice, leading to a lengthened life span of the mice. Our results also suggest that IDH2 disruption suppresses LPS-induced proinflammatory cytokine production, resulting from an inhibition of the NF-κB signaling axis in an α-KG-dependent manner. In conclusion, disruption of IDH2 leads to a decrease in α-KG levels, and the activation of NF-κB in response to LPS is attenuated by reduction of α-KG levels, which eventually reduces the inflammatory response in the lung during LPS-induced ALI. The present study supports the rationale for targeting IDH2 as an important therapeutic strategy for the treatment of systemic inflammatory response syndromes, particularly ALI.
急性肺损伤（ALI）是一种呼吸系统的急性衰竭，死亡率高得令人无法接受，因此急需有效的治疗方法。免疫细胞（如白细胞和巨噬细胞）的浸润导致了 ALI 的炎症反应，其特征是在暴露于各种病原体相关分子（如微生物来源的脂多糖（LPS）的肺组织中，过度产生促炎介质。α-酮戊二酸（α-KG）是一种关键的代谢中间产物，作为一种促炎代谢物，通过 NF-κB 信号通路，负责 LPS 诱导的促炎细胞因子的产生。已报道线粒体 NADP 依赖性异柠檬酸脱氢酶（IDH2）是一种必需的酶，可催化异柠檬酸转化为 α-KG，并同时产生 NADPH。因此，我们使用 IDH2 缺陷小鼠评估了 IDH2 在 LPS 诱导的 ALI 中的作用。我们观察到 LPS 诱导的炎症和肺损伤在 IDH2 缺陷小鼠中减轻，导致小鼠的寿命延长。我们的结果还表明，IDH2 缺失抑制了 LPS 诱导的促炎细胞因子的产生，这是由于 α-KG 依赖性方式抑制了 NF-κB 信号轴。总之，IDH2 的缺失导致 α-KG 水平降低，并且通过降低 α-KG 水平减轻了 LPS 诱导的 NF-κB 的激活，从而在 LPS 诱导的 ALI 期间减轻了肺部的炎症反应。本研究支持将 IDH2 作为治疗全身性炎症反应综合征（特别是 ALI）的重要治疗策略的原理。
