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

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.