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Int J Biol Sci 2015; 11(5):525-535. doi:10.7150/ijbs.10927

Research Paper

NOD2 is Involved in the Inflammatory Response after Cerebral Ischemia-Reperfusion Injury and Triggers NADPH Oxidase 2-Derived Reactive Oxygen Species

Huiqing Liu1, Xinbing Wei1, Lingjun Kong1, Xiaoqian Liu1,2, Li Cheng1, Shi Yan3, Xiumei Zhang1, Lin Chen1✉

1. Department of Pharmacology, School of Medicine, Shandong University, Wenhua West Road 44, Jinan, Shandong 250012, P.R. China.
2. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Ministry of Education of China), School of Pharmacy, Yantai University, Qingquan Road 30, Yantai, Shandong 264005, P.R. China.
3. Department of Obstetrics and Gynaecology, Qilu Hospital of Shandong University, Wenhua West Road 107, Jinan, Shandong 250012, P.R. China.

Abstract

Background: Increasing evidences suggest that innate immunity is involved in cerebral ischemia-reperfusion (I/R) injury, but the liable innate immune receptors have not been completely elucidated. Here, we explored the role of the nucleotide-binding oligomerization domain (NOD)2, a member of the cytosolic NOD-like receptor family, in acute focal cerebral I/R injury.

Methods: An in vivo middle cerebral artery occlusion (MCAO) model that in wild type (WT) and NOD2 deficient (NOD2-/-) mice and in vitro model of oxygen glucose deprivation and reoxygenation (OGD/R) in cultured primary microglia and astrocytes were used to investigate the expression of NOD2 and explore the roles of NOD2 in ischemic stroke.

Results: Our results showed that NOD2 expression was significantly increased in microglia and astrocytes in response to the I/R insult. Pretreatment with muramyl dipeptide, an extrinsic ligand of NOD2, significantly increased the infarct volume and neurological dysfunction in mice subjected to MCAO. Genetic ablation of the NOD2 gene significantly improved stroke outcomes and reduced inflammation, as evidenced by a lower expression of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα in conjunction with attenuated activation of nuclear factor κB (NF-κB), p38 mitogen activated protein kinases (MAPK) and JNK. Moreover, NOD2 deficiency prevented the upregulation of the NADPH oxidase (NOX) 2 and ROS generation induced by I/R. Mechanistically, NOD2-induced production of IL-6 in primary cultured microglia was mediated through activation of NOX2.

Conclusions: This study showed the contribution of NOD2 to inflammatory response and provided direct evidence that NOX2-mediated oxidative stress as an important target molecule linked NOD2 to inflammatory damage in ischemic stroke. Pharmacological targeting of NOD2-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.

Keywords: Nucleotide-binding oligomerization domain (NOD)2, cerebral ischemia-reperfusion, NADPH oxidase, NF-κB, MAPK, inflammation.

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How to cite this article:
Liu H, Wei X, Kong L, Liu X, Cheng L, Yan S, Zhang X, Chen L. NOD2 is Involved in the Inflammatory Response after Cerebral Ischemia-Reperfusion Injury and Triggers NADPH Oxidase 2-Derived Reactive Oxygen Species. Int J Biol Sci 2015; 11(5):525-535. doi:10.7150/ijbs.10927. Available from http://www.ijbs.com/v11p0525.htm