Center for Anti-Inflammatory Therapeutics, School of Dental Medicine and Department of Pharmacology, School of Medicine, Boston University, Boston, MA 02118.
Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):E5059-68. doi: 10.1073/pnas.1320862110. Epub 2013 Dec 9.
The purpose of this study was to elucidate the role of nucleotide binding oligomerization domain-containing protein 2 (NOD2) signaling in atherosclerosis and periodontal bone loss using an Apolipoprotein E(-/-) (ApoE(-/-)) mouse model based on the proposed role of NOD2 in inflammation. NOD2(-/-)ApoE(-/-) and ApoE(-/-) mice fed a standard chow diet were given an oral gavage of Porphyromonas gingivalis for 15 wk. NOD2(-/-)ApoE(-/-) mice exhibited significant increases in inflammatory cytokines, alveolar bone loss, cholesterol, and atherosclerotic lesions in the aorta and the heart compared with ApoE(-/-) mice. In contrast, ApoE(-/-) mice injected i.p. with Muramyl DiPeptide (MDP) to stimulate NOD2 and given an oral gavage of P. gingivalis displayed a reduction of serum inflammatory cytokines, alveolar bone loss, cholesterol, and atherosclerotic lesions in the aorta and aortic sinus compared with ApoE(-/-) mice orally challenged but injected with saline. A reduction in body weight gain was observed in ApoE(-/-) mice fed a high-fat diet (HFD) and injected with MDP compared with ApoE(-/-) mice fed a high-fat diet but injected with saline. MDP treatment of bone marrow-derived macrophages incubated with P. gingivalis increased mRNA expressions of NOD2, Toll-like receptor 2, myeloid differentiation primary response gene 88, and receptor-interacting protein-2 but reduced the expressions of inhibitor of NF-κB kinase-β, NF-κB, c-Jun N-terminal kinase 3, and TNF-α protein levels compared with saline control, highlighting pathways involved in MDP antiinflammatory effects. MDP activation of NOD2 should be considered in the treatment of inflammatory processes affecting atherosclerosis, periodontal bone loss ,and possibly, diet-induced weight gain.
本研究旨在通过载脂蛋白 E 基因敲除（ApoE(-/-)）小鼠模型阐明核苷酸结合寡聚化结构域包含蛋白 2（NOD2）信号在动脉粥样硬化和牙周骨丢失中的作用，该模型基于 NOD2 在炎症中的作用。将 NOD2(-/-)ApoE(-/-)和 ApoE(-/-)小鼠用标准饲料喂养，并给予牙龈卟啉单胞菌口服灌胃 15 周。与 ApoE(-/-)小鼠相比，NOD2(-/-)ApoE(-/-)小鼠表现出炎症细胞因子、牙槽骨丢失、胆固醇和主动脉及心脏动脉粥样硬化病变的显著增加。相比之下，用 Muramyl DiPeptide（MDP）腹腔注射刺激 NOD2并给予牙龈卟啉单胞菌口服灌胃的 ApoE(-/-)小鼠与仅用生理盐水口服挑战的 ApoE(-/-)小鼠相比，血清炎症细胞因子、牙槽骨丢失、胆固醇和主动脉及主动脉窦中的动脉粥样硬化病变减少。与仅用生理盐水腹腔注射的 ApoE(-/-)小鼠相比，用高脂肪饮食（HFD）喂养并注射 MDP 的 ApoE(-/-)小鼠体重增加减少。与生理盐水对照相比，用牙龈卟啉单胞菌孵育的骨髓源性巨噬细胞中 MDP 处理增加了 NOD2、Toll 样受体 2、髓样分化初级反应基因 88 和受体相互作用蛋白 2 的 mRNA 表达，但降低了 NF-κB 激酶-β、NF-κB、c-Jun N-末端激酶 3 和 TNF-α蛋白水平，突出了 MDP 抗炎作用涉及的途径。在治疗影响动脉粥样硬化、牙周骨丢失和可能的饮食诱导体重增加的炎症过程时，应考虑 MDP 对 NOD2 的激活作用。
