Role of JMJD3 and histone modifications in intermittent hypoxia‐induced neuroinflammation (1120.6)

Abstract

Microglial phenotypic plasticity enables them to sense and respond to a variety of stimuli. While much of this plasticity involves transcriptional gene regulation that is highly susceptible to epigenetic modulation, little is known about how post‐translational histone modifications regulate microglial activities. We have shown that intermittent hypoxia (IH), a hallmark of sleep apnea, induces microglial inflammation in vivo, but mechanisms underlying IH‐induced microglial activation are unknown. The Jumonji gene family of histone demethylases are hypoxia‐sensitive, and JMJD3 is known to regulate macrophage inflammatory processes, but nothing is known about its regulation of microglial activities, or its role in IH‐induced neuroinflammation. Thus, using in vivo and in vitro models we tested the hypothesis that JMJD3 is necessary for IH‐induced microglial inflammation. In vivo, JMJD3 mRNA is upregulated in microglia immunomagnetically isolated from the cortex and hippocampus of IH‐treated animals, with a time course that correlates with inflammatory gene induction. To test the requirement of JMJD3 in IH‐induced microglial gene expression, we exposed microglial cell cultures to IH in the presence and absence of the small molecule JMJD3 inhibitor GSK‐J4 (7.5μM). IH increased JMJD3 mRNA levels which correlated with a decrease in histone H3 lysine 27 (H3K27) trimethylation, the enzymatic target of JMJD3 activity. IH‐induced IL‐6, IL‐1β, iNOS, and COX‐2 pro‐inflammatory gene expression was blocked in the presence of GSK‐J4, suggesting a critical role of JMJD3 and H3K27 demethylation in IH‐induced inflammation. This is the first study to investigate a Jumonji demethylase in the context of IH, and the first to link IH‐induced microglial inflammation to JMJD3 activities.Grant Funding Source: Supported by NIH R01 HL111598 and the Graduate Women in Science Ruth Dickie Fellowship