Abstract
BackgroundCircadian rhythm is an important player for reproduction. Rev-erbα, a significant clock gene, is involved in regulating cell differentiation, inflammation and metabolism. Macrophage polarization plays crucial roles in immune tolerance at the maternal-fetus interface, which also modulates the initiation and resolution of inflammation. Alteration of macrophage polarization induces adverse pregnancy outcomes such as infertility, recurrent spontaneous abortion and preterm labor.ResultsDecidual macrophages from LPS-induced mice abortion model displayed M1-like bias, accompanied by decreased expression of Rev-erbα. SR9009, an agonist of Rev-erbα, may reduce lipopolysaccharide (LPS)-induced M1 polarization of macrophages via activation of PI3K but not NF-κB signaling pathway. Furthermore, SR9009 could reduce M1-like polarization of decidual macrophages induced by LPS and attenuate LPS-induced resorption rates in mice model.ConclusionsBoth in vivo and in vitro experiments demonstrated that the pharmacological activation of Rev-erbα using SR9009 could attenuate the effect of LPS on macrophage polarization and protect pregnancy. This study may provide a potential therapeutic strategy for miscarriage induced by inflammation.
Highlights
Circadian rhythm is an important player for reproduction
M1-like polarization and downregulated expression of rev-erbα in decidual macrophages (dMφs) were observed in LPS-induced mice abortion model LPS has been widely used to establish various animal models, such as inflammatory diseases and spontaneous abortion [22, 23]
Consistent with our previous studies that LPS treatment in vitro suppress the expression of Rev-erbα in human endometrial stroma cells (ESCs) [21], the expression of Rev-erbα in decidual tissue from mice treated with LPS was dramatically downregulated
Summary
Circadian rhythm is an important player for reproduction. Rev-erbα, a significant clock gene, is involved in regulating cell differentiation, inflammation and metabolism. The circadian rhythm is regulated by clock genes in a transcriptionaltranslational loop. (Bmal1) and circadian locomotor output cycles kaput (Clock) are two core clock genes. BMAL1-CLOCK heterodimers modulate the transcription of clock genes with E-box sequence such as Per, Cry, Rev-erbα. In the transcriptional-translational feedback loop, Reverbα is an important clock gene and its protein directly represses the transcription of Bmal1 [1, 3]. Rev-erbα, as a transcription factor, is reported to be involved in regulation of behavior rhythm, metabolism, autophagy and inflammation [4,5,6,7]. Rev-erbα may be an important therapeutic target of multiple diseases
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