Xuan Dongying, Han Qianqian, Tu Qisheng, Zhang Lan, Yu Liming, Murry Dana, Tu Tianchi, Tang Yin, Lian Jane B, Stein Gary S, Valverde Paloma, Zhang Jincai, Chen Jake
Department of Periodontology, Guangdong Provincial Stomatological Hospital, Southern Medical University, Guangzhou, China.
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts.
J Cell Physiol. 2016 May;231(5):1090-6. doi: 10.1002/jcp.25201. Epub 2015 Oct 6.
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.
新出现的证据表明，表观遗传机制在巨噬细胞极化和炎症过程中调节信号方面发挥着重要作用。JMJD3是一种JmjC家族组蛋白去甲基化酶，是M2极化所必需的，也是脂多糖（LPS）有效诱导多个M1基因所必需的。然而，在肥胖背景下JMJD3对炎症的影响仍不清楚。为了解决这一不足，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出的巨噬细胞中JMJD3的表达。结果表明，肥胖时JMJD3表达下调。脂联素（APN）是脂肪组织分泌的一种因子，在肥胖时表达下调，其作用是将巨噬细胞极化从M1转换为M2，从而减轻慢性炎症。有趣的是，我们的结果表明，APN有助于上调JMJD3，减少肥胖脂肪组织中的巨噬细胞浸润，并且在受到牙龈卟啉单胞菌LPS（pg.lps）攻击时，消除从DIO小鼠分离的腹腔巨噬细胞中JMJD3的上调。为了阐明在炎症背景下APN和JMJD3在巨噬细胞转化中的相互作用，我们设计了在患有实验性牙周炎的APN（-/-）小鼠体内以及从APN（-/-）小鼠分离的巨噬细胞体外进行APN的功能缺失和功能获得实验。首次发现，APN有助于减少牙周炎相关的骨质流失，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表达促进抗炎性巨噬细胞极化，这为以巨噬细胞为中心的表观遗传治疗策略提供了依据。
