Impaired autophagy with augmented apoptosis in a Th1/Th2-imbalanced placental micromilieu is associated with spontaneous preterm birth

Abstract

Background: Despite decades of research, the pathogenesis of spontaneous preterm birth (PTB) remains largely unknown. Limited currently available data on PTB pathogenesis are based on rodent models, which do not accurately reflect the complexity of the human placenta across gestation. While much study has focused on placental infection and inflammation associated with PTB, two key potentially important cellular events in the placenta—apoptosis and autophagy—remained less explored. Understanding the role of these processes in the human placenta may unravel currently ill-understood processes in the pathomechanism of PTB.Methods: To address this necessity, we conducted qRT-PCR and ELISA assays on placental villous tissue from 20 spontaneous preterm and 20 term deliveries, to assess the inter-relationships between inflammation, apoptosis, and autophagy in villous tissue in order to clarify their roles in the pathogenesis of PTB.Results: We found disrupted balance between pro-apoptotic BAX and anti-apoptotic BCL2 gene/protein expression in preterm placenta, which was associated with significant reduction of BCL2 and increase of BAX proteins along with upregulation of active CASP3 and CASP8 suggesting augmented apoptosis in PTB. In addition, we detected impaired autophagy in the same samples, evidenced by significant accumulation of autophagosome cargo protein p62/SQSTM1 in the preterm villous placentas, which was associated with simultaneous downregulation of an essential autophagy gene ATG7 and upregulation of Ca2+-activated cysteine protease CAPN1. Placental aggregation of p62 was inversely correlated with newborn birth weight, suggesting a potential link between placental autophagy impairment and fetal development. These two aberrations were detected in a micromilieu where the genes of the Th2 cytokines IL10 and IL13 were downregulated, suggesting an alteration in the Th1/Th2 immune balance in the preterm placenta.Conclusion: Taken together, our observations suggest that impaired autophagy and augmented apoptosis in a Th1/Th2 imbalanced placental micro-environment may be associated with the pathogenesis of spontaneous PTB.

Differences in autophagy marker levels at birth in preterm vs. term infants

“…This is consistent with Cao et al, who did not observe a difference in placental protein levels of Beclin-1 33 and Akram et al, who described no difference in gene expression of Beclin-1 (BECN1) between preterm and term placental tissue, despite increased p62 protein levels in the preterm placentas. 34 Conversely to our findings, Cao et al observed lower levels of LC3-II in early preterm compared to term placental tissue. 33 Although we have no clear explanation for this discrepancy, we suspect the different methodology to be the main reason.…”

“…The plausibility of our findings is supported by prior studies, which have focused on placental tissue analyses. Similarly to our observations, they found more p62 in preterm placental tissue, 33,34 although Cao et al observed the differences only between early preterm (<32 weeks of GA) and term placentas. 33 Furthermore, consistent to our findings, Vassallo et al reported lower SIRT1 in endothelial colony-forming cells (ECFCs) in the cord blood of preterm infants.…”

“…Firstly, this was done in partially adjusted models (center adjusted (Basel/Bern)). Secondly, the models were adjusted for risk factors selected according to the literature search [29][30][31][32][33][34] and previous analyses in our cohort. 35 These were SGA, mode of delivery, sex, birth order, maternal smoking during pregnancy and study center.…”

Exploring the Importance of Differential Expression of Autophagy Markers in Term Placentas from Late-Onset Preeclamptic Pregnancies

“…NUP62 has previously been evidenced to be accumulated in preterm villous placentas, associated with a downregulation of the autophagy route. This impairment was also found to be related to a lower birth weight, suggesting that autophagy homeostasis is key for fetal growth [36]. Recent studies have found different results in LO-PE patients, where mRNA levels of this protein were less expressed but protein expression was higher, as determined through enzyme-linked immunosorbent assay (ELISA) techniques [37].…”

The landscape of implantation and placentation: deciphering the function of dynamic RNA methylation at the maternal-fetal interface

“…In early-onset pre-eclamptic placentas and human trophoblast cells exposed to hypoxia and endoplasmic reticulum stresses, pyroptosis is suggested to represent a significant inflammatory mechanism ( 217 ). Current evidence suggests that impaired autophagy and increased apoptosis in a placental microenvironment with Th1/Th2 imbalance are associated with spontaneous preterm birth ( 218 ).…”