Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages

Abstract

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 (Jenke et al., 2014), 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.

Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice

“…Consistent with peripheral inflammatory studies (Satoh et al ., ; Masuda et al ., ), our data suggested that microglial M1 and M2 phenotypes are also regulated by IRF5 and IRF4, respectively. Emerging data have demonstrated the IRF5/4 signaling was implicated in neurodegenerative (Zhu et al ., ; Song et al ., ) and infectious (Takaoka et al ., ; Balkhi et al ., ; Satoh et al ., ; Xuan et al ., ) diseases, and indicated that IRF5/4 are the key determinants for macrophage polarization upon inflammatory stimuli (Al Mamun & Liu, ). The present study found the expression of IRF5/4 in ischemic microglia is up‐regulated in a time‐dependent manner that is closely correlated with M1/2 phenotype, respectively, suggesting microglia share the same mechanism as that in peripheral monocytes to respond to self‐antigens.…”

Adipose, Bone, and Myeloma: Contributions from the Microenvironment

“…Dio2, PGC1α, and FOXC2) [23] is much higher than white adipose tissue (WAT) expression and in certain conditions, such as in caloric restriction (starvation or anorexia), WAT and MAT respond in opposite manners: while WAT decreases, MAT increases [26]. Brown adipose tissue (BAT), WAT and MAT also have been found to express very different levels of numerous adipokines [27]. In addition to the unique physiology of MAT, the close physical proximity of MAT and MM cells suggests unique, bidirectional signaling between MM cells and BM adipocytes unlike signaling between WAT and MM cells.…”

Epigenetic regulation in monocyte/macrophage: A key player during atherosclerosis

“…48 In a research, it was found that adiponectin contributed to anti-inflammatory macrophage polarization by regulating JMJD3 expression, thus reducing macrophage infiltration. 49 Besides JMJD3, the absence of sirtuin-2 (SIRT2) promoted inflammatory responses by up-regulating the acetylation of NF-κB, thus reducing the M2-associated anti-inflammatory responses. 50 DNA methylation and transcription factor regulation are also involved in macrophage polarization.…”