An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment

Abstract

Macrophages are implicated in the local inflammatory response that accompanies spontaneous preterm labor/birth; however, their role is poorly understood. We hypothesized that decidual macrophages undergo an M1 polarization during spontaneous preterm labor and that PPARγ activation via rosiglitazone would attenuate the macrophage-mediated inflammatory response, preventing preterm birth. Herein, we show that: 1) decidual macrophages undergo an M1-like polarization during spontaneous term and preterm labor; 2) M2-like macrophages are more abundant than M1-like macrophages in decidual tissue; 3) decidual M2-like macrophages are reduced in preterm pregnancies compared to term pregnancies, regardless of the presence of labor; 4) decidual macrophages express high levels of TNF and IL12, but low levels of PPARγ, during spontaneous preterm labor; 5) decidual macrophages from women who underwent spontaneous preterm labor display plasticity by M1↔M2 polarization in vitro; 6) incubation with rosiglitazone reduces the expression of TNF and IL12 in decidual macrophages from women who underwent spontaneous preterm labor; and 7) treatment with rosiglitazone reduces the rate of LPS-induced preterm birth and improves neonatal outcomes by reducing the systemic pro-inflammatory response in B6 mice and down-regulating mRNA and protein expression of NFκB, TNF, and IL10 in decidual and myometrial macrophages. In summary, we demonstrated that decidual M1-like macrophages are associated with spontaneous preterm labor, and that PPARγ activation via rosiglitazone can attenuate the macrophage-mediated pro-inflammatory response, preventing preterm birth and improving neonatal outcomes. These findings suggest that the PPARγ pathway is a new molecular target for future preventative strategies for spontaneous preterm labor/birth.

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

“…PPARγ is expressed in the choriodecidual tissues [77], including decidual macrophages [78], where it was suggested to participate in the process of labor [79]. Recently, we reported that PPARγ activation (via rosiglitazone) attenuates the pro-inflammatory response at the maternal-fetal interface induced by a microbial product [78] or activation of invariant natural killer T cells [55]. Altogether, these data suggest that the choriodecidual leukocytes express PPARγ in order to dampen the pro-inflammatory microenvironment that accompanies the process of labor.…”

PPARgamma Expression is Diminished in Macrophages of Recurrent Miscarriage Placentas

“…PPAR depletion leads to fetal loss in early pregnancy due to the missing PPAR expression and extended placental defects [39]. In addition, decidual M1-like macrophage polarization events are associated with PPAR modulation strategies [14]. Therefore the PPAR pathway is a new molecular target for future preventive strategies for the treatment of spontaneous and recurrent miscarriages.…”

“…Not only trophoblast cells express PPAR but also macrophages [14]. Macrophages play a key role in immune response and they can respond to environmental stimuli by acquiring specific phenotypes [15].…”

The decidua of preeclamptic-like BPH/5 mice exhibits an exaggerated inflammatory response during early pregnancy

“…CD11c hi macrophages express more IL-10 than their CD11c low counterparts. Furthermore, both populations of macrophages exhibit characteristics of M1 (proinflammatory) and M2 (tissue-remodeling) polarization (Houser et al, 2011; Xu et al, 2016). As mentioned earlier, we analyzed macrophages using two different gating strategies.…”