Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages.
Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages.
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DOI：
10.1002/jcp.25201
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发表时间：
2016-05
影响因子：
5.6
通讯作者：
Chen J
中科院分区：
文献类型：
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作者：
Xuan D;Han Q;Tu Q;Zhang L;Yu L;Murry D;Tu T;Tang Y;Lian JB;Stein GS;Valverde P;Zhang J;Chen J
新的证据表明表观遗传机制在巨噬细胞极化和炎症过程中调节信号中发挥着重要作用。 JMJD3 是 M2 极化所必需的 JmjC 家族组蛋白去甲基化酶，也是脂多糖 (LPS) 有效诱导多个 M1 基因所必需的。然而，JMJD3 对肥胖背景下炎症的影响仍不清楚。为了解决这一缺陷，我们首先检测了从饮食诱导肥胖（DIO）小鼠的骨髓和脂肪组织中分离的巨噬细胞中 JMJD3 的表达。结果表明，JMJD3 在肥胖中下调。脂联素 (APN) 是一种由脂肪组织分泌的因子，在肥胖时会下调，其功能是将巨噬细胞极化从 M1 转变为 M2，从而减轻慢性炎症。有趣的是，我们的结果表明，当用牙龈卟啉单胞菌 LPS (pg.lps) 攻击时，APN 有助于 JMJD3 上调，减少肥胖脂肪组织中的巨噬细胞浸润，并消除从 DIO 小鼠分离的腹膜巨噬细胞中 JMJD3 的上调。为了阐明炎症背景下巨噬细胞转化中 APN 和 JMJD3 的相互作用，我们设计了患有实验性牙周炎的 APN−/− 小鼠体内 APN 功能丧失和获得功能实验，以及使用从 APN −/− 小鼠中分离的巨噬细胞进行体外 APN 功能丧失和获得功能实验。我们首次发现 APN 有助于减少牙周炎相关的骨丢失、调节 JMJD3 和 IRF4 表达以及巨噬细胞浸润。因此，可以推断APN可能通过调节JMJD3的表达而有助于抗炎巨噬细胞极化，这为以巨噬细胞为中心的表观遗传治疗策略提供了基础。
Emerging evidence suggests an important role for epigenetic mechanisms in modulating signals during macrophage polarization and inflammation. JMJD3, a JmjC family histone demethylase necessary for M2 polarization is also required for effective induction of multiple M1 genes by lipopolysaccharide (LPS). However, the effects of JMJD3 to inflammation in the context of obesity remains unknown. To address this deficiency, we firstly examined the expression of JMJD3 in macrophage isolated from bone marrow and adipose tissue of diet induced obesity (DIO) mice. The results indicated that JMJD3 was down-regulated in obesity. Adiponectin (APN), a factor secreted by adipose tissue which is down-regulated in obesity, functions to switch macrophage polarization from M1 to M2, thereby attenuating chronic inflammation. Intriguingly, our results indicated that APN contributed to JMJD3 up-regulation, reduced macrophage infiltration in obese adipose tissue, and abolished the up-regulation of JMJD3 in peritoneal macrophages isolated from DIO mice when challenged with Porphyromonas gingivalis LPS (pg.lps). To elucidate the interaction of APN and JMJD3 involved in macrophage transformation in the context of inflammation, we designed the loss and gain-function experiments of APN in vivo with APN−/− mice with experimental periodontitis and in vitro with macrophage isolated from APN −/− mice. For the first time, we found that APN can help to reduce periodontitis-related bone loss, modulate JMJD3 and IRF4 expression and macrophage infiltration. Therefore, it can be inferred that APN may contribute to anti-inflammation macrophage polarization by regulating JMJD3 expression, which provides a basis for macrophage-centered epigenetic therapeutic strategies.