Circadian rhythm‐associated Rev‐erbα modulates polarization of decidual macrophage via the PI3K/Akt signaling pathway

Abstract Problem: Circadian rhythms are involved not only in the repair and regeneration of the immune system, but may also be associated with regulation of inflammation and immune responses. Rev‐erbα could constitute a link between immunity and circadian rhythms since it is a transcription factor that regulates circadian rhythms and has functions in multiple physiological and pathological processes. Decidual macrophages (dMφs) play crucial roles in immune balance at the maternal‐fetal interface, and abnormal macrophage polarization is related to adverse pregnancy outcomes, such as infertility, recurrent spontaneous abortion, and preterm labor. However, whether Rev‐erbα could modulate the polarization of macrophages is unknown. Methods of study: In this study, we analyzed the phenotype of dMφs and the expression of Rev‐erbα in dMφs from normal pregnancies and miscarriages. The effect of Rev‐erbα on macrophage polarization was evaluated by its knockdown or pharmacological activation. The mechanism by which the Rev‐erbα agonist SR9009 regulates macrophage polarization was also estimated. Results: A type‐1 macrophage (M1)‐like dominance was observed in dMφs from human miscarriages, with a decreased expression of Rev‐erbα compared to that from normal pregnancies. Rev‐erbα knockdown promoted M1 polarization in macrophages differentiated from the THP1 cell line, whereas pharmacological activation of Rev‐erbα by SR9009 induced type‐2 macrophage (M2)‐like polarization in dMφs. Furthermore, we found that SR9009 induced M2 polarization in macrophages differentiated from the U937 cell line via the PI3K/Akt signaling pathway. Conclusion: Rev‐erbα may play an essential role in macrophage polarization. These findings might help elucidate the role of Rev‐erbα in regulating the differentiation and functions of macrophages and suggest a therapeutic target for pregnancy loss and pregnancy complications.