Disruption of IDH2 attenuates lipopolysaccharide-induced inflammation and lung injury in an alpha-ketoglutarate-dependent manner

Abstract

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. alpha-Ketoglutarate (alpha-KG) is a key metabolic intermediate and acts as a pro-inflammatory metabolite, which is responsible for LPS-induced proinflammatory cytokine production through NF-kappa B signaling pathway. Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme catalyzing the conversion of isocitrate to alpha-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-kappa B signaling axis in an alpha-KG-dependent manner. In conclusion, disruption of IDH2 leads to a decrease in alpha-KG levels, and the activation of NF-kappa B in response to LPS is attenuated by reduction of alpha-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. (C) 2018 Elsevier Inc. All rights reserved.