NAD kinase is a protective metabolic enzyme against systemic inflammation

Identification: Wu, Jing-Yiing


NAD kinase is a protective metabolic enzyme against systemic inflammation
Jing-Yiing Wu1, Chang-Ching Yeh1,2, Hui-chen Lin1, Yi-Ting Hsieh1, Guan-Lin Lee1 and Cheng-Chin Kuo1
1Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; 2Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan
Immune homeostasis is important for maintaining cellular physiological functions. Inappropriate activation of TLR signaling by pathogen components and endogenous molecules is thought to be one mechanism initiating and driving excessive inflammation which disrupts immune homeostasis and results in inflammatory syndrome and diseases. Recently, using omic approach we identified that the expression level of NAD kinase was increased in TLR agonists-stimulated mouse macrophage RAW264.7 cells. NAD kinase is a key enzyme for the de novo NADP+/NADPH biosynthesis, which has an important function in regulating anti-oxidative defense system by maintaining the NADP+/NADPH pool. Our results indicated that NAD kinase negatively control TLR2-, TLR4- and TLR9-mediated production of IL-6 and reactive oxygen species (ROS) in macrophages via p38/PI3K/Akt and JNK dependent pathway. Notably, the IL-6 and ROS levels were elevated in NADK-deficient mice as compared with those of wild type mice. In addition, activation of TLR2, TLR3 and TLR4 increased IL-6 levels in NADK-deficient macrophages. The ROS levels were increased in NADK-deficient macrophages treated with LPS or H2O2. Furthermore, the pathological alterations of the kidney and lung occurred in NADK-deficient mice. Lung injury of NADK-deficient mice revealed a wider alveolar diameter, which was restored with injection of antioxidant, mitoTempo, in postnatal periods of development. These results suggest that deficiency of NAD kinase in mice leads to severe inflammatory pathogenesis and organ injury. Thus, we propose that NAD kinase may act as a regulator of redox-inflammation homeostasis.


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