Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms.
Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms.
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DOI：
10.1161/atvbaha.116.307373
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Upchurch GR Jr
中科院分区：
文献类型：
--
作者：
Sharma AK;Salmon MD;Lu G;Su G;Pope NH;Smith JR;Weiss ML;Upchurch GR Jr
Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that macrophage-produced high mobility group box1 (HMGB1) production is dependent on NADPH oxidase (Nox2) which leads to increase in IL-17 production resulting in AAA formation and that treatment with human mesenchymal stem cells (MSCs) can attenuate this process thereby inhibiting AAA formation. Human aortic tissue demonstrated a significant increase in HMGB1 expression in AAA patients compared to controls. An elastase-perfusion model of AAA demonstrated a significant increase in HMGB1 production in C57BL/6 (wild type; WT) mice, which was attenuated by MSC treatment. Furthermore, anti-HMGB1 antibody treatment of WT mice attenuated AAA formation, IL-17 production and immune cell infiltration compared to elastase-perfused WT mice on day 14. Elastase-perfused Nox2−/y mice demonstrated a significant attenuation of HMGB1 and IL-17 production, cellular infiltration, matrix metalloproteinase activity and AAA formation compared to WT mice on day 14. In vitro studies showed that elastase-treated macrophages from WT mice, but not Nox2−/y mice, produced HMGB1, which was attenuated by MSC treatment. The production of macrophage-dependent HMGB1 involved Nox2 activation and superoxide anion production, which was mitigated by MSC treatment. These results demonstrate that macrophage-produced HMGB1 leads to aortic inflammation and acts as a trigger for CD4+ T cell produced IL-17 during AAA formation. HMGB1 release is dependent on Nox2 activation, which can be inhibited by MSCs leading to attenuation of proinflammatory cytokines, especially IL-17, and protection against AAA formation.
